5A0E

Crystal structure of cyclophilin D in complex with CsA analogue, JW47.

Summary for 5A0E

• Entry DOI: 10.2210/pdb5a0e/pdb
• Descriptor: PEPTIDYL-PROLYL CIS-TRANS ISOMERASE F, MITOCHONDRIAL, JW47 (3 entities in total)
• Functional Keywords: isomerase, cyclophilin d, cyp d, ppif, cyclosporin a, csa, jw47, mitochondrial permeability transition pore, ptp, peptidylprolyl cis-trans isomerase, cyclophilin
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 4
• Total formula weight: 38232.07

Authors

Warne, J.,Pryce, G.,Hill, J.,Shi, X.,Lenneras, F.,Puentes, F.,Kip, M.,Hilditch, L.,Walker, P.,Simone, M.,Chan, A.W.E.,Towers, G.,Coker, A.R.,Duchen, M.,Szabadkai, G.,Baker, D.,Selwood, D.L. (deposition date: 2015-04-19, release date: 2015-12-30, Last modification date: 2024-01-10)

Primary citation

Warne, J.,Pryce, G.,Hill, J.,Shi, X.,Lenneras, F.,Puentes, F.,Kip, M.,Hilditch, L.,Walker, P.,Simone, M.I.,Chan, A.W.E.,Towers, G.J.,Coker, A.R.,Duchen, M.R.,Szabadkai, G.,Baker, D.,Selwood, D.L.
Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects Against Neuro-Degeneration in Experimental Multiple Sclerosis.
J.Biol.Chem., 291:4356-, 2016

PubMed Abstract: The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.

PubMed: 26679998
DOI: 10.1074/JBC.M115.700385

Experimental method

X-RAY DIFFRACTION (1.25 Å)