8EJX

Crystal structure of human cyclophilin D (CypD) with in complex with the covalently bound Ebselen inhibitor

8EJX の概要

• エントリーDOI: 10.2210/pdb8ejx/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase F, mitochondrial, N-phenyl-2-selanylbenzamide (3 entities in total)
• 機能のキーワード: 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: 18031.40

構造登録者

Lovell, S.,Battaile, K.P.,Yan, S. (登録日: 2022-09-19, 公開日: 2023-10-18, 最終更新日: 2026-03-04)

主引用文献

Samanta, S.,Akhter, F.,Roy, A.,Chen, D.,Turner, B.,Wang, Y.,Clemente, N.,Wang, C.,Swerdlow, R.H.,Battaile, K.P.,Lovell, S.,Yan, S.F.,Yan, S.S.
New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer's disease.
Brain, 147:1710-1725, 2024

PubMed Abstract: Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer's disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer's disease. However, there is currently no effective CypD inhibitor for Alzheimer's disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer's disease mitochondrial and glycolytic bioenergetics in Alzheimer's disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer's disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer's disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer's disease- and amyloid-β-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer's disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer's disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.

PubMed: 38146639
DOI: 10.1093/brain/awad432

実験手法

X-RAY DIFFRACTION (1.65 Å)