2cmt
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THE STRUCTURE OF REDUCED CYCLOPHILIN A FROM S. MANSONI
OverviewOverview
Treatment of Schistosomiasis, a widespread human parasitic disease caused, by the helminth parasites of the genus Schistosoma, relies mainly on one, chemotherapeutic agent, praziquantel, although several other compounds, exert anti-parasitic effects. One such compound is the immunosuppressant, cyclosporin A, which has been shown to significantly diminish worm burden, in mice infected with S. mansoni. Given the well-established interaction, between cyclosporin A and the cyclophilin superfamily of peptidyl-prolyl, cis-trans isomerases, we solved the structure of cyclophilin A from S., mansoni (SmCypA) by X-ray crystallography in the reduced and oxidised, states, at 1.5A and 1.8A resolution respectively. Oxidised SmCypA contains, a disulphide bridge between two C-terminal cysteines (C122 and C126). This, is the first example of a cyclophilin containing this disulphide bridge., Parallel functional studies suggest a mechanism for regulation of SmCypA, activity via oxidation of its thiol groups; in fact, while oxidised SmCypA, is inactive, reduced SmCypA is an efficient isomerase active at nanomolar, levels with a kcat/Km of 1.1 x 10;7 M-1s-1 and it is inhibited by, cyclosporin A (IC50 of 14 +/- 4nM). The lack of conservation of this, cysteine couple within the CypA superfamily, their close proximity to the, active site and the importance of thiol groups for PPIase activity render, this structural feature a challenge for the development of alternative and, more effective anti-schistosomiasis inhibitors and may in addition imply, an alternative function of SmCypA in the schistosome.
About this StructureAbout this Structure
2CMT is a Single protein structure of sequence from Schistosoma mansoni with as ligand. Active as Peptidylprolyl isomerase, with EC number 5.2.1.8 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
The three-dimensional structure of two redox states of cyclophilin-A from schistosoma mansoni: Evidence for redox- regulation of peptidyl-prolyl cis-trans isomerase activity., Gourlay LJ, Angelucci F, Baiocco P, Boumis G, Brunori M, Bellelli A, Miele AE, J Biol Chem. 2007 Jun 25;. PMID:17591771
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