The Experts below are selected from a list of 261063 Experts worldwide ranked by ideXlab platform
Steven E Shoelson - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of the hnf4α Ligand Binding domain in complex with endogenous fatty acid Ligand
Journal of Biological Chemistry, 2002Co-Authors: Sirano Dhepaganon, Karen Duda, Melanie Iwamoto, Steven E ShoelsonAbstract:Abstract HNF4α is an orphan member of the nuclear receptor family with prominent functions in liver, gut, kidney and pancreatic β cells. We have solved the x-ray crystal structure of the HNF4α Ligand Binding domain, which adopts a canonical fold. Two conformational states are present within each homodimer: an open form with α helix 12 (α12) extended and collinear with α10 and a closed form with α12 folded against the body of the domain. Although the protein was crystallized without added Ligands, the Ligand Binding pockets of both closed and open forms contain fatty acids. The carboxylic acid headgroup of the fatty acid ion pairs with the guanidinium group of Arg226 at one end of the Ligand Binding pocket, while the aliphatic chain fills a long, narrow channel that is lined with hydrophobic residues. These findings suggest that fatty acids are endogenous Ligands for HNF4α and establish a framework for understanding how HNF4α activity is enhanced by Ligand Binding and diminished by MODY1 mutations.
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crystal structure of the hnf4α Ligand Binding domain in complex with endogenous fatty acid Ligand
Journal of Biological Chemistry, 2002Co-Authors: Sirano Dhepaganon, Karen Duda, Melanie Iwamoto, Young In Chi, Steven E ShoelsonAbstract:HNF4 alpha is an orphan member of the nuclear receptor family with prominent functions in liver, gut, kidney and pancreatic beta cells. We have solved the x-ray crystal structure of the HNF4 alpha Ligand Binding domain, which adopts a canonical fold. Two conformational states are present within each homodimer: an open form with alpha helix 12 (alpha 12) extended and collinear with alpha 10 and a closed form with alpha 12 folded against the body of the domain. Although the protein was crystallized without added Ligands, the Ligand Binding pockets of both closed and open forms contain fatty acids. The carboxylic acid headgroup of the fatty acid ion pairs with the guanidinium group of Arg(226) at one end of the Ligand Binding pocket, while the aliphatic chain fills a long, narrow channel that is lined with hydrophobic residues. These findings suggest that fatty acids are endogenous Ligands for HNF4 alpha and establish a framework for understanding how HNF4 alpha activity is enhanced by Ligand Binding and diminished by MODY1 mutations.
Sirano Dhepaganon - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of the hnf4α Ligand Binding domain in complex with endogenous fatty acid Ligand
Journal of Biological Chemistry, 2002Co-Authors: Sirano Dhepaganon, Karen Duda, Melanie Iwamoto, Steven E ShoelsonAbstract:Abstract HNF4α is an orphan member of the nuclear receptor family with prominent functions in liver, gut, kidney and pancreatic β cells. We have solved the x-ray crystal structure of the HNF4α Ligand Binding domain, which adopts a canonical fold. Two conformational states are present within each homodimer: an open form with α helix 12 (α12) extended and collinear with α10 and a closed form with α12 folded against the body of the domain. Although the protein was crystallized without added Ligands, the Ligand Binding pockets of both closed and open forms contain fatty acids. The carboxylic acid headgroup of the fatty acid ion pairs with the guanidinium group of Arg226 at one end of the Ligand Binding pocket, while the aliphatic chain fills a long, narrow channel that is lined with hydrophobic residues. These findings suggest that fatty acids are endogenous Ligands for HNF4α and establish a framework for understanding how HNF4α activity is enhanced by Ligand Binding and diminished by MODY1 mutations.
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crystal structure of the hnf4α Ligand Binding domain in complex with endogenous fatty acid Ligand
Journal of Biological Chemistry, 2002Co-Authors: Sirano Dhepaganon, Karen Duda, Melanie Iwamoto, Young In Chi, Steven E ShoelsonAbstract:HNF4 alpha is an orphan member of the nuclear receptor family with prominent functions in liver, gut, kidney and pancreatic beta cells. We have solved the x-ray crystal structure of the HNF4 alpha Ligand Binding domain, which adopts a canonical fold. Two conformational states are present within each homodimer: an open form with alpha helix 12 (alpha 12) extended and collinear with alpha 10 and a closed form with alpha 12 folded against the body of the domain. Although the protein was crystallized without added Ligands, the Ligand Binding pockets of both closed and open forms contain fatty acids. The carboxylic acid headgroup of the fatty acid ion pairs with the guanidinium group of Arg(226) at one end of the Ligand Binding pocket, while the aliphatic chain fills a long, narrow channel that is lined with hydrophobic residues. These findings suggest that fatty acids are endogenous Ligands for HNF4 alpha and establish a framework for understanding how HNF4 alpha activity is enhanced by Ligand Binding and diminished by MODY1 mutations.
Lili Duan - One of the best experts on this subject based on the ideXlab platform.
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interaction entropy a new paradigm for highly efficient and reliable computation of protein Ligand Binding free energy
Journal of the American Chemical Society, 2016Co-Authors: Lili Duan, Xiao Liu, John Z H ZhangAbstract:Efficient and reliable calculation of protein–Ligand Binding free energy is a grand challenge in computational biology and is of critical importance in drug design and many other molecular recognition problems. The main challenge lies in the calculation of entropic contribution to protein–Ligand Binding or interaction systems. In this report, we present a new interaction entropy method which is theoretically rigorous, computationally efficient, and numerically reliable for calculating entropic contribution to free energy in protein–Ligand Binding and other interaction processes. Drastically different from the widely employed but extremely expensive normal mode method for calculating entropy change in protein–Ligand Binding, the new method calculates the entropic component (interaction entropy or −TΔS) of the Binding free energy directly from molecular dynamics simulation without any extra computational cost. Extensive study of over a dozen randomly selected protein–Ligand Binding systems demonstrated that...
Haruki Nakamura - One of the best experts on this subject based on the ideXlab platform.
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prediction of Ligand Binding sites of proteins by molecular docking calculation for a random Ligand library
Protein Science, 2011Co-Authors: Yoshifumi Fukunishi, Haruki NakamuraAbstract:A new approach to predicting the Ligand-Binding sites of proteins was developed, using protein-Ligand docking computation. In this method, many compounds in a random library are docked onto the whole protein surface. We assumed that the true Ligand-Binding site would exhibit stronger affinity to the compounds in the random library than the other sites, even if the random library did not include the Ligand corresponding to the true Binding site. We also assumed that the affinity of the true Ligand-Binding site would be correlated to the docking scores of the compounds in the random library, if the Ligand-Binding site was correctly predicted. We call this method the molecular-docking Binding-site finding (MolSite) method. The MolSite method was applied to 89 known protein-Ligand complex structures extracted from the Protein Data Bank, and it predicted the correct Binding sites with about 80–99% accuracy, when only the single top-ranked site was adopted. In addition, the average docking score was weakly correlated to the experimental protein-Ligand Binding free energy, with a correlation coefficient of 0.44.
Dino Moras - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of a heterodimeric complex of rar and rxr Ligand Binding domains
Molecular Cell, 2000Co-Authors: William Bourguet, Pierre Chambon, Hinrich Gronemeyer, Jean Marie Wurtz, Valerie Vivat, Dino MorasAbstract:Abstract The crystal structure of a heterodimer between the Ligand-Binding domains (LBDs) of the human RARα bound to a selective antagonist and the constitutively active mouse RXRαF318A mutant shows that, pushed by a bulky extension of the Ligand, RARα helix H12 adopts an antagonist position. The unexpected presence of a fatty acid in the Ligand-Binding pocket of RXRαF318A is likely to account for its apparent "constitutivity." Specific conformational changes suggest the structural basis of pure and partial antagonism. The RAR–RXR heterodimer interface is similar to that observed in most nuclear receptor (NR) homodimers. A correlative analysis of 3D structures and sequences provides a novel view on dimerization among members of the nuclear receptor superfamily.
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the nuclear receptor Ligand Binding domain structure and function
Current Opinion in Cell Biology, 1998Co-Authors: Dino Moras, Hinrich GronemeyerAbstract:Abstract In the past few years our understanding of nuclear receptor action has dramatically improved as a result of the elucidation of the crystal structures of the empty (apo) Ligand-Binding domains of the nuclear receptor and of complexes formed by the nuclear receptor's Ligand-Binding domain bound to agonists and antagonists. Furthermore, the concomitant identification and functional analysis of co-regulators (transcriptional intermediary factors [TIFs], comprising co-activators and co-repressors) previously predicted from squelching studies, have deepened this understanding. Recent data have provided the structural basis for the specific recognition of Ligands and the molecular mechanisms of agonism and antagonism, enabling us to gain a comprehensive view of the early steps of nuclear receptor action.
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a canonical structure for the Ligand Binding domain of nuclear receptors
Nature Structural & Molecular Biology, 1996Co-Authors: Jean Marie Wurtz, William Bourguet, Pierre Chambon, Dino Moras, Jean Paul Renaud, Valerie Vivat, Hinrich GronemeyerAbstract:The ability of nuclear receptors (NRs) to activate transcription of target genes requires the Binding of cognate Ligands to their Ligand-Binding domains (LBDs). Information provided by the three-dimensional structures of the unLiganded RXRα and the Liganded RARγ LBDs has been incorporated into a general alignment of the LBDs of all NRs. A twenty amino-acid region constitutes a NR-specif ic signature and contains most of the conserved residues that stabilize the core of the canonical fold of NR LBDs. A common Ligand-Binding pocket, involving predominantly hydrophobic residues, is inferred by homology modelling of the human RXRα and glucocorticoid receptor Ligand-Binding sites according to the RARγ holo-LBD structure. Mutant studies support these models, as well as a general mechanism for Ligand-induced activation deduced from the comparison of the transcriptionally active RARγ holo- and inactive RXRα apo-LBD structures.
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crystal structure of the Ligand Binding domain of the human nuclear receptor rxr alpha
Nature, 1995Co-Authors: William Bourguet, Marc Ruff, Pierre Chambon, Hinrich Gronemeyer, Dino MorasAbstract:The crystal structure of the human retinoid-X receptor RXR-α Ligand-Binding domain reveals a previously undiscovered fold of an antiparallel α-helical sandwich, packed as dimeric units. Two helices and one loop form the homodimerization surface, and hydrophobic heptad repeats participate in stabilizing the fold. The existence of a Ligand-Binding pocket is proposed that would allow 9-cis retinoic acid to interact with different functional modules, including the AF-2 activating domain. Several lines of evidence indicate that the overall structure is a prototype fold of Ligand-Binding domains of nuclear receptors.