PDBsum entry 5a0e

Isomerase

PDB id: 5a0e

Contents

Protein chains

165 a.a.

11 a.a.

Waters ×304

PDB id:

5a0e

Name:

Isomerase

Title:

Crystal structure of cyclophilin d in complex with csa analogue, jw47.

Structure:

Peptidyl-prolyl cis-trans isomerase f, mitochondrial. Chain: a, b. Synonym: ppiase f, 5.2.1.8, cyclophilin d, cyp-d, cypd, cyclophilin f, mitochondrial cyclophilin, cyp-m, rotamase f. Engineered: yes. Mutation: yes. Jw47. Chain: c, e. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: plyss. Synthetic: yes. Cylindrocarpon lucidum. Organism_taxid: 301100

Resolution:

1.25Å R-factor: 0.100 R-free: 0.131

Authors:

J.Warne,G.Pryce,J.Hill,X.Shi,F.Lenneras,F.Puentes,M.Kip,L.Hilditch, P.Walker,M.Simone,A.W.E.Chan,G.Towers,A.R.Coker,M.Duchen, G.Szabadkai,D.Baker,D.L.Selwood

Key ref:

J.Warne et al. (2016). Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis. J Biol Chem, 291, 4356-4373. PubMed id: 26679998 DOI: 10.1074/jbc.M115.700385

Date:

19-Apr-15 Release date: 30-Dec-15

Protein chains

P30405  (PPIF_HUMAN) -  Peptidyl-prolyl cis-trans isomerase F, mitochondrial from Homo sapiens

Seq: 207 a.a.

Struc: 165 a.a.*

Protein chains

No UniProt id for this chain

Struc: 11 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.5.2.1.8 - peptidylprolyl isomerase.
• Reaction: [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1074/jbc.M115.700385

J Biol Chem 291:4356-4373 (2016)

PubMed id: 26679998

Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis.

J.Warne, G.Pryce, J.M.Hill, X.Shi, F.Lennerås, F.Puentes, M.Kip, L.Hilditch, P.Walker, M.I.Simone, A.W.Chan, G.J.Towers, A.R.Coker, M.R.Duchen, G.Szabadkai, D.Baker, D.L.Selwood.

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.