6GJR

Cyclophilin A complexed with tri-vector ligand 9.

6GJR の概要

• エントリーDOI: 10.2210/pdb6gjr/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase A, ethyl 2-[[(4-aminophenyl)methyl-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyl]carbamoyl]amino]ethanoate (3 entities in total)
• 機能のキーワード: cyclophilins, cypa, inhibitor, ppiase, complex, isomerase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18383.88

構造登録者

Georgiou, C.,De Simone, A.,Walkinshaw, M.D.,Michel, J. (登録日: 2018-05-16, 公開日: 2018-11-07, 最終更新日: 2024-01-17)

主引用文献

De Simone, A.,Georgiou, C.,Ioannidis, H.,Gupta, A.A.,Juarez-Jimenez, J.,Doughty-Shenton, D.,Blackburn, E.A.,Wear, M.A.,Richards, J.P.,Barlow, P.N.,Carragher, N.,Walkinshaw, M.D.,Hulme, A.N.,Michel, J.
A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors.
Chem Sci, 10:542-547, 2019

PubMed Abstract: Cyclophilins (Cyps) are a major family of drug targets that are challenging to prosecute with small molecules because the shallow nature and high degree of conservation of the active site across human isoforms offers limited opportunities for potent and selective inhibition. Herein a computational approach based on molecular dynamics simulations and free energy calculations was combined with biophysical assays and X-ray crystallography to explore a flip in the binding mode of a reported urea-based Cyp inhibitor. This approach enabled access to a distal pocket that is poorly conserved among key Cyp isoforms, and led to the discovery of a new family of sub-micromolar cell-active inhibitors that offer unprecedented opportunities for the development of next-generation drug therapies based on Cyp inhibition. The computational approach is applicable to a broad range of organic functional groups and could prove widely enabling in molecular design.

PubMed: 30746096
DOI: 10.1039/c8sc03831g

実験手法

X-RAY DIFFRACTION (1.69 Å)