4TOT

Crystal structure of rat cyclophilin D in complex with a potent nonimmunosuppressive inhibitor

4TOT の概要

• エントリーDOI: 10.2210/pdb4tot/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002115
• 分子名称: Peptidyl-prolyl cis-trans isomerase F, mitochondrial, nonimmunosuppressive inhibitor, HEXAETHYLENE GLYCOL, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, cyclosporin, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• 細胞内の位置: Mitochondrion matrix : P29117
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 77541.41

構造登録者

Knapp, M.S.,Elling, R.A. (登録日: 2014-06-06, 公開日: 2014-11-12, 最終更新日: 2024-04-03)

主引用文献

Fu, J.,Tjandra, M.,Becker, C.,Bednarczyk, D.,Capparelli, M.,Elling, R.,Hanna, I.,Fujimoto, R.,Furegati, M.,Karur, S.,Kasprzyk, T.,Knapp, M.,Leung, K.,Li, X.,Lu, P.,Mergo, W.,Miault, C.,Ng, S.,Parker, D.,Peng, Y.,Roggo, S.,Rivkin, A.,Simmons, R.L.,Wang, M.,Wiedmann, B.,Weiss, A.H.,Xiao, L.,Xie, L.,Xu, W.,Yifru, A.,Yang, S.,Zhou, B.,Sweeney, Z.K.
Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition.
J.Med.Chem., 57:8503-8516, 2014

PubMed Abstract: Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

PubMed: 25310383
DOI: 10.1021/jm500862r

実験手法

X-RAY DIFFRACTION (2.39 Å)