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6vif

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

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:
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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cornelison JL, Cato ML, Johnson AM, D'Agostino EH, Melchers D, Patel AB, Mays SG, Houtman R, Ortlund EA, Jui NT. Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition. Bioorg Med Chem Lett. 2020 Aug 15;30(16):127293. doi: 10.1016/j.bmcl.2020.127293., Epub 2020 May 30. PMID:32631515 doi:http://dx.doi.org/10.1016/j.bmcl.2020.127293