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PDBsum entry 2cmt

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Isomerase PDB id
2cmt
Jmol
Contents
Protein chain
164 a.a.
Ligands
ACT
Waters ×100

References listed in PDB file
Key reference
Title 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.
Authors L.J.Gourlay, F.Angelucci, P.Baiocco, G.Boumis, M.Brunori, A.Bellelli, A.E.Miele.
Ref. J Biol Chem, 2007, 282, 24851-24857. [DOI no: 10.1074/jbc.M702714200]
PubMed id 17591771
Abstract
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 Schistosoma mansoni. Given the well established interaction between cyclosporin A and the cyclophilin superfamily of peptidylprolyl cis-trans isomerases, we solved the structure of cyclophilin A from S. mansoni (SmCypA) by x-ray crystallography in the reduced and oxidized states at 1.5 and 1.8 A of resolution, respectively. Oxidized SmCypA contains a disulfide bridge between two C-terminal cysteines (Cys-122 and Cys-126). This is the first example of a cyclophilin containing this disulfide bridge. Parallel functional studies suggest a mechanism for regulation of SmCypA activity via oxidation of its thiol groups; in fact, whereas oxidized SmCypA is inactive, reduced SmCypA is an efficient isomerase active at nanomolar levels with a k(cat)/K(m) of 1.1 x 10(7) M(-1) s(-1), and it is inhibited by cyclosporin A (IC(50) of 14 +/- 4 nM). 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 peptidyl-prolyl cis-trans isomerase 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.
Figure 1.
FIGURE 1. Sequence alignment of SmCypA and hCYP33. The amino acid sequences of SmCypA (residues 1–172) and the C-terminal domain of human cyclophilin-33 (residues 139–300) were aligned using the T-Coffee multiple alignment program (37). Cysteines and the conserved tryptophan are highlighted by shading. Active site amino acids (Arg-62, Phe-67, Met-68, Asn-109, Phe-120, Trp-128, Leu-129, and His-133) are boxed. Identical residues are indicated by an asterisk; similar and less similar residues are indicated by double and single dots, respectively. Numbering follows the SmCypA sequence.
Figure 2.
FIGURE 2. A, superimposition of the three-dimensional structures of SmCypA^red (blue ribbon) and SmCypA^ox (magenta), highlighting the N and C termini. B, detailed view of the substrate/inhibitor binding site of SmCypA^red (the view is 180° rotated with respect to panel A). Cys-122, Cys-126, and residues forming the pockets listed in Table 2 are shown in ball-and-stick format. The red circles indicate the approximate location of pockets 1, 2, and 3. C, as in B, shown is the substrate/inhibitor binding site of SmCypA^ox, containing the disulfide bond. D, magnified view of the active site loop. The interactions of water molecule (W40) with the sulfur atoms of Cys-122 and Cys-126 are shown together with their distances from the carbonyl groups of the loop, which make contact with the water. This figure was generated using PyMOL (34).
The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 24851-24857) copyright 2007.
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