| Structural highlights
5a0e is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | NonStd Res: | , , , , , |
| Activity: | Peptidylprolyl isomerase, with EC number 5.2.1.8 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum |
Function
[PPIF_HUMAN] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probablity of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis.[1] [2]
Publication Abstract from PubMed
The mitochondrial permeability transition pore (PT pore) is a recognised drug target for neurodegenerative conditions such as multiple sclerosis (MS) and for ischaemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, ppif) is a positive regulator of the pore and genetic downregulation or knockout 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, immune-suppression and toxicity. We therefore designed and synthesised a new mitochondrially-targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine (CsA). X-ray analysis was used to validate the design concept and biological evaluation revealed selective cellular inhibition of CypD and the PT pore with reduced cellular toxicity compared to CsA. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis (MS), 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.
Selective inhibition of the mitochondrial permeability transition pore protects against neuro-degeneration in experimental multiple sclerosis.,Warne J, Pryce G, Hill J, Shi X, Lenneras F, Puentes F, Kip M, Hilditch L, Walker P, Simone MI, Chan AW, Towers GJ, Coker A, Duchen MR, Szabadkai G, Baker D, Selwood DL J Biol Chem. 2015 Dec 17. pii: jbc.M115.700385. PMID:26679998[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Eliseev RA, Malecki J, Lester T, Zhang Y, Humphrey J, Gunter TE. Cyclophilin D interacts with Bcl2 and exerts an anti-apoptotic effect. J Biol Chem. 2009 Apr 10;284(15):9692-9. doi: 10.1074/jbc.M808750200. Epub 2009, Feb 19. PMID:19228691 doi:http://dx.doi.org/10.1074/jbc.M808750200
- ↑ Vaseva AV, Marchenko ND, Ji K, Tsirka SE, Holzmann S, Moll UM. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell. 2012 Jun 22;149(7):1536-48. doi: 10.1016/j.cell.2012.05.014. PMID:22726440 doi:10.1016/j.cell.2012.05.014
- ↑ Warne J, Pryce G, Hill J, Shi X, Lenneras F, Puentes F, Kip M, Hilditch L, Walker P, Simone MI, Chan AW, Towers GJ, Coker A, Duchen MR, Szabadkai G, Baker D, Selwood DL. Selective inhibition of the mitochondrial permeability transition pore protects against neuro-degeneration in experimental multiple sclerosis. J Biol Chem. 2015 Dec 17. pii: jbc.M115.700385. PMID:26679998 doi:http://dx.doi.org/10.1074/jbc.M115.700385
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