4ple

Human Nuclear Receptor Liver Receptor Homologue-1, LRH-1, Bound to an E. Coli Phospholipid and a Fragment of TIF-2

spinqualitylabelsall models 4ple, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ple is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CPS, EPH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NR5A2_HUMAN Binds to the sequence element 5'-AACGACCGACCTTGAG-3' of the enhancer II of hepatitis B virus genes, a critical cis-element of their expression and regulation. May be responsible for the liver-specific activity of enhancer II, probably in combination with other hepatocyte transcription factors. Key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver. May also contribute to the regulation of pancreas-specific genes and play important roles in embryonic development. Publication Abstract from PubMed Phospholipids (PLs) are unusual signaling hormones sensed by the nuclear receptor liver receptor homolog 1 (LRH 1), which has evolved a novel allosteric pathway to support appropriate interaction with coregulators depending on ligand status. LRH-1 plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of metabolic and neoplastic diseases. While the prospect of modulating LRH-1 via small molecules is exciting, the molecular mechanism linking PL structure to transcriptional coregulator preference is unknown. Previous studies showed that binding to an activating PL ligand, such as dilauroylphosphatidylcholine (DLPC), favors LRH-1s interaction with transcriptional coactivators to upregulate gene expression. Both crystallographic and solution based structural studies showed that DLPC binding drives unanticipated structural fluctuations outside of the canonical activation surface in an alternate activation function (AF) region, encompassing the beta-sheet-H6 region of the protein. However, the mechanism by which dynamics in the alternate AF influences coregulator selectivity remains elusive. Here we pair x-ray crystallography with molecular modeling to identify an unexpected allosteric network that traverses the protein ligand binding pocket and links these two elements to dictate selectivity. We show that communication between the alternate AF region and classical AF2 dictates the strength of the coregulator interaction. This work offers the first glimpse into the conformational dynamics that drive this unusual PL-mediated nuclear hormone receptor activation. Unexpected Allosteric Network Contributes to LRH-1 Coregulator Selectivity.,Musille PM, Kossmann BR, Kohn JA, Ivanov I, Ortlund EA J Biol Chem. 2015 Nov 9. pii: jbc.M115.662874. PMID:26553876 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Liver receptor homolog-1

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