6VIF

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

6VIF の概要

• エントリーDOI: 10.2210/pdb6vif/pdb
• 分子名称: Nuclear receptor subfamily 5 group A member 2, Nuclear receptor coactivator 2, N-[(8beta,11alpha,12alpha)-8-{[methyl(phenyl)amino]methyl}-1,6:7,14-dicycloprosta-1(6),2,4,7(14)-tetraen-11-yl]sulfuric diamide, ... (4 entities in total)
• 機能のキーワード: ligand-binding domain, nuclear receptor, small molecule, agonist, nuclear protein, liver receptor homolog-1
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30521.32

構造登録者

Cato, M.L.,Ortlund, E.A. (登録日: 2020-01-13, 公開日: 2020-06-10, 最終更新日: 2023-10-11)

主引用文献

Cornelison, J.L.,Cato, M.L.,Johnson, A.M.,D'Agostino, E.H.,Melchers, D.,Patel, A.B.,Mays, S.G.,Houtman, R.,Ortlund, E.A.,Jui, N.T.
Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition.
Bioorg.Med.Chem.Lett., 30:127293-127293, 2020

PubMed Abstract: 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.

PubMed: 32631515
DOI: 10.1016/j.bmcl.2020.127293

実験手法

X-RAY DIFFRACTION (2.26 Å)