6vif | pdb_00006vif

Human LRH-1 ligand-binding domain bound to agonist cpd 15 and fragment of coregulator TIF-2

spinqualitylabelsall models 6vif, resolution 2.26Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6vif is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.26Å Ligands: QY4 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 LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded. We have developed a new synthetic approach to overcome this limitation, identified that bridgehead substitution is necessary for LRH-1 activation, and described an alternative class of bridgehead substituents for effective LRH-1 agonist development. We determined the crystal structure of LRH-1 bound to a bridgehead-modified compound, revealing a promising opportunity to target novel regions of the ligand binding pocket to alter LRH-1 target gene expression. Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition.,Cornelison JL, Cato ML, Johnson AM, D'Agostino EH, Melchers D, Patel AB, Mays SG, Houtman R, Ortlund EA, Jui NT Bioorg Med Chem Lett. 2020 Aug 15;30(16):127293. doi: 10.1016/j.bmcl.2020.127293., Epub 2020 May 30. PMID:32631515 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Liver receptor homolog-1

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