9F0I

Human Cyclophilin D in complex with fragment

これはPDB形式変換不可エントリーです。

9F0I の概要

• エントリーDOI: 10.2210/pdb9f0i/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase F, mitochondrial, ~{N}-(2-ethyl-1,2,3,4-tetrazol-5-yl)thiophene-2-carboxamide (3 entities in total)
• 機能のキーワード: cyclophilin d ppiase, 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: 18005.53

構造登録者

Silva, D.O.,Graedler, U.,Bandeiras, T.M. (登録日: 2024-04-16, 公開日: 2025-04-30, 最終更新日: 2026-04-08)

主引用文献

Silva, D.O.,Freitas, M.C.,Malta, C.F.,Martins, M.T.,Sousa, P.M.F.,Matias, P.M.,Schwarz, D.,Ventura, M.R.,Gradler, U.,Bandeiras, T.M.
Structure-based design of pyrazole derivatives targeting the human Cyclophilin D binding site.
Int.J.Biol.Macromol., :151496-151496, 2026

PubMed Abstract: Mitochondrial permeability transition pore (MPTP) dysregulation can be correlated with a variety of human diseases including multiple sclerosis, cardiovascular and neurological diseases. Human Cyclophilin D is a known MPTP regulator and although devoid of deep orthosteric sites, it is believed it can be targeted to develop clinically relevant candidates. Fragment-based drug discovery is a powerful approach for such drug-targets and we revisited a panel of 52 fragment hits by X-ray crystallography, which remained structurally elusive from a previous fragment screening campaign. Using two CypD mutants in a systematic parallel approach combining co-crystallization and soaking techniques (FragInc approach - from Fragment Incubation), new high-resolution crystal structures of CypD-fragment complexes were obtained. We identified a pyrazolo[1,5-a]pyrimidin-2(1H)-one fragment binding to a cleft in-between the known CypD S1' and S2 pockets. These structural insights guided the chemical synthesis of four new molecules to address simultaneously the novel pyrazolo binding pocket and the S2 site, and their crystal structures in complex with CypD were determined. This work opens new perspectives for structure-based drug design of novel tri-vector inhibitors targeting human CypD and proposes a parallel multi-technique methodology to address low-affinity fragments by X-ray crystallography.

PubMed: 41881208
DOI: 10.1016/j.ijbiomac.2026.151496

実験手法

X-RAY DIFFRACTION (1.4 Å)