The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Don C Wiley - One of the best experts on this subject based on the ideXlab platform.
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crystallographic analysis of endogenous peptides associated with hla dr1 suggests a common polyproline it like conformation
2016Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Robert G Urban, Jack L Strominger, Joan C Gorgat, Don C WileyAbstract:The structure of the human major histocom- patibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus en- terotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC mol- ecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DRI-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine res- idues of the DRI molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
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crystallographic analysis of endogenous peptides associated with hla dr1 suggests a common polyproline ii like conformation for bound peptides
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Joan C Gorga, Robert G Urban, Jack L Strominger, Don C WileyAbstract:Abstract The structure of the human major histocompatibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus enterotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC molecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DR1-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine residues of the DR1 molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
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invariant chain made in escherichia coli has an exposed n terminal segment that blocks antigen binding to hla dr1 and a trimeric c terminal segment that binds empty hla dr1
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Seongjoon Park, Scheherazade Sadeghnasseri, Don C WileyAbstract:Invariant chain (Ii), a membrane glycoprotein, binds class II major histocompatibility complex (MHC) glycoproteins, probably via its class II-associated Ii peptide (CLIP) segment, and escorts them toward antigen-containing endosomal compartments. We find that a soluble, trimeric ectodomain of Ii expressed and purified from Escherichia coli blocks peptide binding to soluble HLA-DR1. Proteolysis indicates that Ii contains two structural domains. The C-terminal two-thirds forms an alpha-helical domain that trimerizes and interacts with empty HLA-DR1 molecules, augmenting rather than blocking peptide binding. The N-terminal one-third, which inhibits peptide binding, is proteolytically susceptible over its entire length. In the trimer, the N-terminal domains act independently with each CLIP segment exposed and free to bind an MHC class II molecule, while the C-terminal domains act as a trimeric unit.
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three dimensional structure of a human class ii histocompatibility molecule complexed with superantigen
Nature, 1994Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Joan C Gorga, Robert G Urban, Jack L Strominger, Young In Chi, Cynthia V Stauffacher, Don C WileyAbstract:The structure of a bacterial superantigen, Staphylococcus aureus enterotoxin B, bound to a human class II histocompatibility complex molecule (HLA-DR1) has been determined by X-ray crystallography. The superantigen binds as an intact protein outside the conventional peptide antigen-binding site of the class II major histocompatibility complex (MHC) molecule. No large conformational changes occur upon complex formation in either the DR1 or the enterotoxin B molecules. The structure of the complex helps explain how different class II molecules and superantigens associate and suggests a model for ternary complex formation with the T-cell antigen receptor (TCR), in which unconventional TCR-MHC contacts are possible.
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Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide
Nature, 1994Co-Authors: Lawrence J. Stern, Jerry H Brown, Theodore S Jardetzky, Joan C Gorga, Robert G Urban, Jack L Strominger, Don C WileyAbstract:An influenza virus peptide binds to HLA-DR1 in an extended conformation with a pronounced twist. Thirty-five per cent of the peptide surface is accessible to solvent and potentially available for interaction with the antigen receptor on T cells. Pockets in the peptide-binding site accommodate five of the thirteen side chains of the bound peptide, and explain the peptide specificity of HLA-DR1. Twelve hydrogen bonds between conserved HLA-DR1 residues and the main chain of the peptide provide a universal mode of peptide binding, distinct from the strategy used by class I histocompatibility proteins.
Lawrence J. Stern - One of the best experts on this subject based on the ideXlab platform.
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crystallographic analysis of endogenous peptides associated with hla dr1 suggests a common polyproline it like conformation
2016Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Robert G Urban, Jack L Strominger, Joan C Gorgat, Don C WileyAbstract:The structure of the human major histocom- patibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus en- terotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC mol- ecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DRI-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine res- idues of the DRI molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
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conformational lability in the class ii mhc 310 helix and adjacent extended strand dictate hla dm susceptibility and peptide exchange
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Corrie Painter, Maria Pia Negroni, Zarixia Zavalaruiz, James E. Evans, Katherine A. Kellersberger, Lawrence J. SternAbstract:HLA-DM is required for efficient peptide exchange on class II MHC molecules, but its mechanism of action is controversial. We trapped an intermediate state of class II MHC HLA-DR1 by substitution of αF54, resulting in a protein with increased HLA-DM binding affinity, weakened MHC-peptide hydrogen bonding as measured by hydrogen-deuterium exchange mass spectrometry, and increased susceptibility to DM-mediated peptide exchange. Structural analysis revealed a set of concerted conformational alterations at the N-terminal end of the peptide-binding site. These results suggest that interaction with HLA-DM is driven by a conformational change of the MHC II protein in the region of the α-subunit 310 helix and adjacent extended strand region, and provide a model for the mechanism of DM-mediated peptide exchange.
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human cytotoxic cd4 t cells recognize hla dr1 restricted epitopes on vaccinia virus proteins a24r and d1r conserved among poxviruses
Journal of Immunology, 2007Co-Authors: Shibani Mitrakaushik, Lawrence J. Stern, John Cruz, Francis A Ennis, Masanori TerajimaAbstract:We previously demonstrated that vaccinia virus (VV)-specific CD4 + cytolytic T cells can persist for >50 years after immunization against smallpox in the absence of re-exposure to VV. Nevertheless, there have been few studies focusing on CD4 + T cell responses to smallpox vaccination. To ensure successful vaccination, a candidate vaccine should contain immunodominant CD4 + T cell epitopes as well as CD8 + T and B cell epitopes. In the present study, we established cytotoxic CD4 + T cell lines from VV-immune donors, which recognize epitopes in VV proteins D1R and A24R in association with HLA-DR1 Ags. Comparisons of sequences between different members of the poxvirus family show that both epitopes are completely conserved among VV, variola viruses, and most mammalian poxviruses, including monkeypox, cowpox, and ectromelia. The CD4 + T cell lines lysed VV-infected, Ag- and peptide-pulsed targets, and the lysis was inhibited by concanamycin A. We also detected these peptide-specific cytolytic and IFN-γ-producing CD4 + T cells in short-term bulk cultures of PBMC from each of the three VV-immune donors tested. These are the first VV-specific CD4 + T cell epitopes identified in humans restricted by one of the most common MHC class II molecules, HLA-DR1, and this information may be useful in analyzing CD4 + T cell responses to pre-existing or new generation VV vaccines against smallpox.
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crystallographic analysis of endogenous peptides associated with hla dr1 suggests a common polyproline ii like conformation for bound peptides
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Joan C Gorga, Robert G Urban, Jack L Strominger, Don C WileyAbstract:Abstract The structure of the human major histocompatibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus enterotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC molecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DR1-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine residues of the DR1 molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
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three dimensional structure of a human class ii histocompatibility molecule complexed with superantigen
Nature, 1994Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Joan C Gorga, Robert G Urban, Jack L Strominger, Young In Chi, Cynthia V Stauffacher, Don C WileyAbstract:The structure of a bacterial superantigen, Staphylococcus aureus enterotoxin B, bound to a human class II histocompatibility complex molecule (HLA-DR1) has been determined by X-ray crystallography. The superantigen binds as an intact protein outside the conventional peptide antigen-binding site of the class II major histocompatibility complex (MHC) molecule. No large conformational changes occur upon complex formation in either the DR1 or the enterotoxin B molecules. The structure of the complex helps explain how different class II molecules and superantigens associate and suggests a model for ternary complex formation with the T-cell antigen receptor (TCR), in which unconventional TCR-MHC contacts are possible.
Jerry H Brown - One of the best experts on this subject based on the ideXlab platform.
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crystallographic analysis of endogenous peptides associated with hla dr1 suggests a common polyproline it like conformation
2016Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Robert G Urban, Jack L Strominger, Joan C Gorgat, Don C WileyAbstract:The structure of the human major histocom- patibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus en- terotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC mol- ecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DRI-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine res- idues of the DRI molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
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crystallographic analysis of endogenous peptides associated with hla dr1 suggests a common polyproline ii like conformation for bound peptides
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Joan C Gorga, Robert G Urban, Jack L Strominger, Don C WileyAbstract:Abstract The structure of the human major histocompatibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus enterotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC molecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DR1-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine residues of the DR1 molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
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three dimensional structure of a human class ii histocompatibility molecule complexed with superantigen
Nature, 1994Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Joan C Gorga, Robert G Urban, Jack L Strominger, Young In Chi, Cynthia V Stauffacher, Don C WileyAbstract:The structure of a bacterial superantigen, Staphylococcus aureus enterotoxin B, bound to a human class II histocompatibility complex molecule (HLA-DR1) has been determined by X-ray crystallography. The superantigen binds as an intact protein outside the conventional peptide antigen-binding site of the class II major histocompatibility complex (MHC) molecule. No large conformational changes occur upon complex formation in either the DR1 or the enterotoxin B molecules. The structure of the complex helps explain how different class II molecules and superantigens associate and suggests a model for ternary complex formation with the T-cell antigen receptor (TCR), in which unconventional TCR-MHC contacts are possible.
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Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide
Nature, 1994Co-Authors: Lawrence J. Stern, Jerry H Brown, Theodore S Jardetzky, Joan C Gorga, Robert G Urban, Jack L Strominger, Don C WileyAbstract:An influenza virus peptide binds to HLA-DR1 in an extended conformation with a pronounced twist. Thirty-five per cent of the peptide surface is accessible to solvent and potentially available for interaction with the antigen receptor on T cells. Pockets in the peptide-binding site accommodate five of the thirteen side chains of the bound peptide, and explain the peptide specificity of HLA-DR1. Twelve hydrogen bonds between conserved HLA-DR1 residues and the main chain of the peptide provide a universal mode of peptide binding, distinct from the strategy used by class I histocompatibility proteins.
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three dimensional structure of the human class ii histocompatibility antigen hla dr1
Nature, 1993Co-Authors: Lawrence J. Stern, Jerry H Brown, Theodore S Jardetzky, Joan C Gorga, Robert G Urban, Jack L Strominger, Don C WileyAbstract:The three-dimensional structure of the class II histocompatibility glycoprotein HLA-DR1 from human B-cell membranes has been determined by X-ray crystallography and is similar to that of class I HLA. Peptides are bound in an extended conformation that projects from both ends of an 'open-ended' antigen-binding groove. A prominent non-polar pocket into which an 'anchoring' peptide side chain fits is near one end of the binding groove. A dimer of the class II αβ heterodimers is seen in the crystal forms of HLA-DR1, suggesting class II HLA dimerization as a mechanism for initiating the cytoplasmic signalling events in T-cell activation.
Theodore S Jardetzky - One of the best experts on this subject based on the ideXlab platform.
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crystallographic analysis of endogenous peptides associated with hla dr1 suggests a common polyproline it like conformation
2016Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Robert G Urban, Jack L Strominger, Joan C Gorgat, Don C WileyAbstract:The structure of the human major histocom- patibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus en- terotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC mol- ecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DRI-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine res- idues of the DRI molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
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interference with t cell receptor hla dr interactions by epstein barr virus gp42 results in reduced t helper cell recognition
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Maaike E Ressing, Theodore S Jardetzky, Daphne Van Leeuwen, Frank A W Verreck, Raquel Gomez, Bianca Heemskerk, Mireille Toebes, Maureen M Mullen, Richard Longnecker, Marco W SchilhamAbstract:Epstein–Barr virus (EBV) persists lifelong in infected hosts despite the presence of antiviral immunity. Many viral antigens are expressed during lytic infection. Thus, for EBV to spread, it must have evolved effective ways to evade immune recognition. Here, we report that HLA class II-restricted antigen presentation to T helper cells is hampered in the presence of the lytic-phase protein gp42. This interference with T cell activation involves association of gp42 with class II peptide complexes. Using HLA-DR tetramers, we identify a block in T cell receptor (TCR)–class II interactions imposed by gp42 as the underlying mechanism. EBV gp42 sterically clashes with TCR Vα-domains as visualized by superimposing the crystal structures for gp42–HLA-DR1 and TCR–MHC class II complexes. Blocking TCR recognition provides a previously undescribed strategy for viral immune evasion.
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crystallographic analysis of endogenous peptides associated with hla dr1 suggests a common polyproline ii like conformation for bound peptides
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Joan C Gorga, Robert G Urban, Jack L Strominger, Don C WileyAbstract:Abstract The structure of the human major histocompatibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus enterotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC molecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DR1-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine residues of the DR1 molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
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three dimensional structure of a human class ii histocompatibility molecule complexed with superantigen
Nature, 1994Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Joan C Gorga, Robert G Urban, Jack L Strominger, Young In Chi, Cynthia V Stauffacher, Don C WileyAbstract:The structure of a bacterial superantigen, Staphylococcus aureus enterotoxin B, bound to a human class II histocompatibility complex molecule (HLA-DR1) has been determined by X-ray crystallography. The superantigen binds as an intact protein outside the conventional peptide antigen-binding site of the class II major histocompatibility complex (MHC) molecule. No large conformational changes occur upon complex formation in either the DR1 or the enterotoxin B molecules. The structure of the complex helps explain how different class II molecules and superantigens associate and suggests a model for ternary complex formation with the T-cell antigen receptor (TCR), in which unconventional TCR-MHC contacts are possible.
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Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide
Nature, 1994Co-Authors: Lawrence J. Stern, Jerry H Brown, Theodore S Jardetzky, Joan C Gorga, Robert G Urban, Jack L Strominger, Don C WileyAbstract:An influenza virus peptide binds to HLA-DR1 in an extended conformation with a pronounced twist. Thirty-five per cent of the peptide surface is accessible to solvent and potentially available for interaction with the antigen receptor on T cells. Pockets in the peptide-binding site accommodate five of the thirteen side chains of the bound peptide, and explain the peptide specificity of HLA-DR1. Twelve hydrogen bonds between conserved HLA-DR1 residues and the main chain of the peptide provide a universal mode of peptide binding, distinct from the strategy used by class I histocompatibility proteins.
Jack L Strominger - One of the best experts on this subject based on the ideXlab platform.
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crystallographic analysis of endogenous peptides associated with hla dr1 suggests a common polyproline it like conformation
2016Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Robert G Urban, Jack L Strominger, Joan C Gorgat, Don C WileyAbstract:The structure of the human major histocom- patibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus en- terotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC mol- ecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DRI-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine res- idues of the DRI molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
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a ph sensitive histidine residue as control element for ligand release from hla dr molecules
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Olaf Rotzschke, Julie M Lau, Maria Hofstatter, Kirsten Falk, Jack L StromingerAbstract:Class II MHC molecules undergo conformational changes on shifts of the pH. As a consequence, low-affinity peptides tightly bound at pH 7.0 can be released at pH 5.0. The imidazole group of histidine is the only amino acid side chain affected within this range. At pH 5.0 the group is positively charged, polar, and hydrophilic, whereas at pH 7.4 it is neutral, apolar, and hydrophobic. In this study, we used soluble forms of HLA-DR and substituted conserved histidine residues with tyrosine, an isosteric analogue to the uncharged form of histidine. The goal of this substitution was to identify crucial His residues by an increase in pH stability of the ligand complex. HLA-DM-mediated release experiments revealed that substitution of His-33 in the α1 domain of the HLA-DR molecule almost doubled the half-life of HLA-DR1/class II-associated invariant-chain peptide complexes. The divergence in the off-rate of WT and H33Y mutated complex was strictly pH-dependent and correlated with the theoretical titration curve of the imidazole group. For both HLA-DR1 and HLA–DR4 molecules the mutation resulted in a shift of class II-associated invariant-chain peptide release curves by up to 0.5 pH units. His-33α1 is present in all HLA-DR and H-2E molecules. It connects the α1 and α2 domains in its noncharged form by hydrophobic interactions with residue Val-136α2. It is located in close proximity to the putative interface with HLA-DM and may function as a pH-sensitive “button,” which is closed at pH 7.0 but opens below pH 6.0 to allow conformational transitions necessary for ligand exchange.
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crystallographic analysis of endogenous peptides associated with hla dr1 suggests a common polyproline ii like conformation for bound peptides
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Joan C Gorga, Robert G Urban, Jack L Strominger, Don C WileyAbstract:Abstract The structure of the human major histocompatibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus enterotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC molecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DR1-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine residues of the DR1 molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
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three dimensional structure of a human class ii histocompatibility molecule complexed with superantigen
Nature, 1994Co-Authors: Theodore S Jardetzky, Lawrence J. Stern, Jerry H Brown, Joan C Gorga, Robert G Urban, Jack L Strominger, Young In Chi, Cynthia V Stauffacher, Don C WileyAbstract:The structure of a bacterial superantigen, Staphylococcus aureus enterotoxin B, bound to a human class II histocompatibility complex molecule (HLA-DR1) has been determined by X-ray crystallography. The superantigen binds as an intact protein outside the conventional peptide antigen-binding site of the class II major histocompatibility complex (MHC) molecule. No large conformational changes occur upon complex formation in either the DR1 or the enterotoxin B molecules. The structure of the complex helps explain how different class II molecules and superantigens associate and suggests a model for ternary complex formation with the T-cell antigen receptor (TCR), in which unconventional TCR-MHC contacts are possible.
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Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide
Nature, 1994Co-Authors: Lawrence J. Stern, Jerry H Brown, Theodore S Jardetzky, Joan C Gorga, Robert G Urban, Jack L Strominger, Don C WileyAbstract:An influenza virus peptide binds to HLA-DR1 in an extended conformation with a pronounced twist. Thirty-five per cent of the peptide surface is accessible to solvent and potentially available for interaction with the antigen receptor on T cells. Pockets in the peptide-binding site accommodate five of the thirteen side chains of the bound peptide, and explain the peptide specificity of HLA-DR1. Twelve hydrogen bonds between conserved HLA-DR1 residues and the main chain of the peptide provide a universal mode of peptide binding, distinct from the strategy used by class I histocompatibility proteins.