The Experts below are selected from a list of 85137 Experts worldwide ranked by ideXlab platform
Xiaoyuan Chen - One of the best experts on this subject based on the ideXlab platform.
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a new 18f labeled bbn rgd peptide Heterodimer with a symmetric linker for prostate cancer imaging
Amino Acids, 2011Co-Authors: Kai Chen, Min Yang, Xiaoyuan ChenAbstract:A peptide Heterodimer comprises two different receptor-targeting peptide ligands. Molecular imaging probes based on dual-receptor targeting peptide Heterodimers exhibit improved tumor targeting efficacy for multi-receptor expressing tumors compared with their parent single-receptor targeting peptide monomers. Previously we have developed bombesin (BBN)-RGD (Arg-Gly-Asp) peptide Heterodimers, in which BBN and RGD are covalently connected with an asymmetric glutamate linker (J Med Chem 52:425–432, 2009). Although 18F-labeled Heterodimers showed significantly better microPET imaging quality than 18F-labeled RGD and BBN monomers in a PC-3 xenograft model which co-expresses gastrin-releasing peptide receptor (GRPR) and integrin αvβ3, tedious Heterodimer synthesis due to the asymmetric nature of glutamate linker restricts their clinical applications. In this study, we report the use of a symmetric linker AEADP [AEADP = 3,3′-(2-aminoethylazanediyl)dipropanoic acid] for the synthesis of BBN-RGD peptide Heterodimer. The 18F-labeled Heterodimer (18F-FB-AEADP-BBN-RGD) showed comparable microPET imaging results with glutamate linked BBN-RGD Heterodimers, indicating that the replacement of glutamate linker with AEADP linker did not affect the biological activities of BBN-RGD Heterodimer. The Heterodimer synthesis is rather easy and straightforward. Because tumors often co-express multiple receptors, the use of a symmetric linker provides a general method of fast assembly of various peptide Heterodimers for imaging multi-receptor expressing tumors.
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Peptide Heterodimers for molecular imaging
Amino Acids, 2010Co-Authors: Xiaoyuan ChenAbstract:One main issue with peptide-based molecular imaging probes is their relatively low tumor affinity and short retention time. To improve peptide binding affinity, multivalency approach has been introduced. Traditionally, this approach involves the use of peptide homodimers or homomultimers in which peptide ligands of the same type are constructed with suitable linkers. Recently, a new approach using peptide Heterodimers has emerged as a promising method for targeting multi-receptor over-expressed tumor cells. Significant affinity enhancements have been observed with peptide Heterodimers compared with their parent peptide monomers. In a peptide Heterodimer, two different peptide ligands capable of targeting two different receptors are covalently linked. The binding modes of peptide Heterodimers can be monovalent or bivalent depending on whether simultaneous binding of two ligands can be achieved. Increased local ligand concentration and improved binding kinetics contribute to enhanced binding in both monovalent- and bivalent binding modes, while multivalency effect also plays an important role in bivalent binding mode. As many tumors overexpress multiple receptors, more peptide Heterodimer-based molecular imaging probes are expected to be developed in future. This review article will discuss the peptide homodimers and Heterodimers for molecular imaging with special emphasis on peptide Heterodimers.
Sebastian Springer - One of the best experts on this subject based on the ideXlab platform.
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stoichiometry of hla class ii invariant chain oligomers
PLOS ONE, 2011Co-Authors: Norbert Koch, Angelika Konig, Martin Zacharias, Sebastian Temme, Jürgen Neumann, Sebastian SpringerAbstract:BACKGROUND: The HLA gene complex encodes three class II isotypes, DR, DQ, and DP. HLA class II molecules are peptide receptors that present antigens for recognition by T lymphocytes. In antigen presenting cells, the assembly of matched α and β subunits to Heterodimers is chaperoned by invariant chain (Ii). Ii forms a homotrimer with three binding sites for class II Heterodimers. The current model of class II and Ii structure states that three αβ Heterodimers bind to an Ii trimer. METHODOLOGY/PRINCIPAL FINDINGS: [corrected] We have now analyzed the composition and size of the complexes of class II and Ii using epitope tagged class II subunits and density gradient experiments. We show here that class II-Ii oligomers consist of one class II Heterodimer associated with one Ii trimer, such that the DR, DQ and DP isotypes are contained within separate complexes with Ii. CONCLUSION/SIGNIFICANCE: We propose a structural model of the class II-Ii oligomer and speculate that the pentameric class II-Ii complex is bent towards the cell membrane, inhibiting the binding of additional class II Heterodimers to Ii.
David M Sabatini - One of the best experts on this subject based on the ideXlab platform.
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architecture of human rag gtpase Heterodimers and their complex with mtorc1
Science, 2019Co-Authors: Madhanagopal Anandapadamanaban, David M Sabatini, Glenn R Masson, Olga Perisic, A Berndt, Jonathan Kaufman, Christopher M Johnson, Balaji Santhanam, Kacper B Rogala, R WilliamsAbstract:The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag Heterodimers is critical for their association with mTORC1. Our cryo–electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the Heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag Heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.
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ragulator and slc38a9 activate the rag gtpases through noncanonical gef mechanisms
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Kuang Shen, David M SabatiniAbstract:The mechanistic target of rapamycin complex 1 (mTORC1) growth pathway detects nutrients through a variety of sensors and regulators that converge on the Rag GTPases, which form Heterodimers consisting of RagA or RagB tightly bound to RagC or RagD and control the subcellular localization of mTORC1. The Rag Heterodimer uses a unique “locking” mechanism to stabilize its active ( GTP RagA–RagC GDP ) or inactive ( GDP RagA–RagC GTP ) nucleotide states. The Ragulator complex tethers the Rag Heterodimer to the lysosomal surface, and the SLC38A9 transmembrane protein is a lysosomal arginine sensor that upon activation stimulates mTORC1 activity through the Rag GTPases. How Ragulator and SLC38A9 control the nucleotide loading state of the Rag GTPases remains incompletely understood. Here we find that Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state. Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP- to the GTP-loaded state, and therefore activates the Rag GTPase Heterodimer. Altogether, Ragulator and SLC38A9 act on the Rag GTPases to activate the mTORC1 pathway in response to nutrient sufficiency.
N. W. Isaacs - One of the best experts on this subject based on the ideXlab platform.
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Crystal structure of human chorionic gonadotropin
Nature, 1994Co-Authors: Adrian J Lapthorn, Joyce W. Lustbader, Allison Littlejohn, D C Harris, K. J. Machin, F J Morgan, Robert E Canfield, N. W. IsaacsAbstract:The three-dimensional structure of human chorionic gonadotropin shows that each of its two different subunits has a similar topology, with three disulphide bonds forming a cystine knot. This same folding motif is found in some protein growth factors. The Heterodimer is stabilized by a segment of the β-subunit which wraps around the α-subunit and is covalently linked like a seat belt by the disulphide Cys 26-Cys 110. This extraordinary feature appears to be essential not only for the association of these Heterodimers but also for receptor binding by the glyco-protein hormones. © 1994 Nature Publishing Group.
Magnus Pfahl - One of the best experts on this subject based on the ideXlab platform.
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retinoid x receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors
Nature, 1992Co-Authors: Xiaokun Zhang, Birgit Hoffmann, P Tran, Gerhart Graupner, Magnus PfahlAbstract:THYROID hormones and retinoic acid function through nuclear receptors that belong to the steroid/thyroid-hormone receptor superfamily (reviewed in refs 1–4). Thyroid hormone receptors (TRs) and retinoic acid receptors (RARs) require auxiliary nuclear proteins for efficient DNA binding5–10. Here we report that retinoid X receptors RXRα (ref. 11) is one of these nuclear proteins. RXRα interacts both with TRs and with RARs, forming Heterodimers in solution that strongly interact with a variety of T3/retinoic acid response elements. Transfection experiments show that RXRα can greatly enhance the transcriptional activity of TR and RAR at low retinoic acid concentrations that do not significantly activate RXRα itself. Thus, RXRα enhances the transcriptional activity of other receptors and its own ligand sensitivity by Heterodimer formation. Our studies reveal a new subclass of receptors and a regulatory pathway controlling nuclear receptor activities by Heterodimer formation.
