8EJX

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

Summary for 8EJX

• Entry DOI: 10.2210/pdb8ejx/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase F, mitochondrial, N-phenyl-2-selanylbenzamide (3 entities in total)
• Functional Keywords: isomerase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 18031.40

Authors

Lovell, S.,Battaile, K.P.,Yan, S. (deposition date: 2022-09-19, release date: 2023-10-18, Last modification date: 2026-03-04)

Primary citation

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 (AD) and plays a crucial role in the development and progression of AD. 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 (mPTP), leading to mitochondrial dysfunction and cell death. Blocking mPTP opening by inhibiting CypD activity is a promising therapeutic approach for AD. However, there is currently no effective CypD inhibitor for AD, 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 nontoxic 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 AD mitochondrial and glycolytic bioenergetics in AD-derived mitochondrial cybrid cells, an ex-vivo human sporadic AD mitochondrial model, and on synaptic function, inflammatory response, and learning and memory in AD mouse models. Inhibition of CypD by Ebselen protects against sporadic AD- and amyloid beta (Aβ)-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of AD mouse models, which is linked to CypD-related mPTP formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including AD, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.

PubMed: 38146639
DOI: 10.1093/brain/awad432

Experimental method

X-RAY DIFFRACTION (1.65 Å)