8SVS

Crystal structure of pregnane X receptor ligand binding domain in complex with SJPYT-328

8SVS の概要

• エントリーDOI: 10.2210/pdb8svs/pdb
• 分子名称: Nuclear receptor subfamily 1 group I member 2, Nuclear receptor coactivator 1 fusion protein,Nuclear receptor coactivator 1, (1P)-N-(5-tert-butyl-2-{[(3S)-hexan-3-yl]oxy}phenyl)-1-(2,4-dimethoxy-5-methylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (3 entities in total)
• 機能のキーワード: pregnane x receptor (pxr), promiscuous ligand-activated protein, nuclear receptor subfamily 1, transcriptional regulator, drug metabolism, transcription
• 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: 80808.57

構造登録者

Garcia-Maldonado, E.,Huber, A.D.,Nithianantham, S.,Miller, D.J.,Chen, T. (登録日: 2023-05-17, 公開日: 2024-05-15, 最終更新日: 2024-06-05)

主引用文献

Garcia-Maldonado, E.,Huber, A.D.,Chai, S.C.,Nithianantham, S.,Li, Y.,Wu, J.,Poudel, S.,Miller, D.J.,Seetharaman, J.,Chen, T.
Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR.
Nat Commun, 15:4054-4054, 2024

PubMed Abstract: Nuclear receptors are ligand-activated transcription factors that can often be useful drug targets. Unfortunately, ligand promiscuity leads to two-thirds of receptors remaining clinically untargeted. PXR is a nuclear receptor that can be activated by diverse compounds to elevate metabolism, negatively impacting drug efficacy and safety. This presents a barrier to drug development because compounds designed to target other proteins must avoid PXR activation while retaining potency for the desired target. This problem could be avoided by using PXR antagonists, but these compounds are rare, and their molecular mechanisms remain unknown. Here, we report structurally related PXR-selective agonists and antagonists and their corresponding co-crystal structures to describe mechanisms of antagonism and selectivity. Structural and computational approaches show that antagonists induce PXR conformational changes incompatible with transcriptional coactivator recruitment. These results guide the design of compounds with predictable agonist/antagonist activities and bolster efforts to generate antagonists to prevent PXR activation interfering with other drugs.

PubMed: 38744881
DOI: 10.1038/s41467-024-48472-1

実験手法

X-RAY DIFFRACTION (2.68 Å)