1qnh
Plasmodium falciparum Cyclophilin (double mutant) complexed with Cyclosporin APlasmodium falciparum Cyclophilin (double mutant) complexed with Cyclosporin A
Structural highlights
FunctionQ25756_PLAFA PPIases accelerate the folding of proteins (By similarity).[RuleBase:RU000493] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides (By similarity).[RuleBase:RU004223] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCyclosporin A (CsA) is a potent anti-malarial compound in vitro and in vivo in mice though better known for its immunosuppressive properties in humans. Crystal structures of wild-type and a double mutant Plasmodium falciparum cyclophilin (PfCyP19 and mPfCyP19) complexed with CsA have been determined using diffraction terms to a resolution of 2.1 A (1 A=0.1 nm). The wild-type has a single PfCyP19/CsA complex per asymmetric unit in space group P1 and refined to an R-work of 0.15 and R-free of 0.19. An altered cyclophilin, with two accidental mutations, Phe120 to Leu in the CsA binding pocket and Leu171 to Trp at the C terminus, presents two complexes per asymmetric unit in the orthorhombic space group P2(1)2(1)2. This refined to an R-work of 0.18 and R-free 0.21. The mutations were identified from the crystallographic analysis and the C-terminal alteration helps to explain the different crystal forms obtained. PfCyP19 shares approximately 61 % sequence identity with human cyclophilin A (hCyPA) and the structures are similar, consisting of an eight-stranded antiparallel beta-barrel core capped by two alpha-helices. The fold creates a hydrophobic active-site, the floor of which is formed by side-chains of residues from four antiparallel beta-strands and the walls from loops and turns. We identified C-H.O hydrogen bonds between the drug and protein that may be an important feature of cyclophilins and suggest a general mode of interaction between hydrophobic molecules. Comparisons with cyclophilin-dipeptide complexes suggests that a specific C-H.O hydrogen bonding interaction may contribute to ligand binding. Residues Ser106, His99 and Asp130, located close to the active site and conserved in most cyclophilins, are arranged in a manner reminiscent of a serine protease catalytic triad. A Ser106Ala mutant was engineered to test the hypothesis that this triad contributes to CyP function. Mutant and wild-type enzymes were found to have similar catalytic properties. The three-dimensional structure of a Plasmodium falciparum cyclophilin in complex with the potent anti-malarial cyclosporin A.,Peterson MR, Hall DR, Berriman M, Nunes JA, Leonard GA, Fairlamb AH, Hunter WN J Mol Biol. 2000 Apr 21;298(1):123-33. PMID:10756109[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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