1qnh

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spinqualitylabelsall models 1qnh, resolution 2.1Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

PLASMODIUM FALCIPARUM CYCLOPHILIN (DOUBLE MUTANT) COMPLEXED WITH CYCLOSPORIN A

Overview

Cyclosporin 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.

About this Structure

1QNH is a Single protein structure of sequence from Plasmodium falciparum and Tolypocladium inflatum. Active as Peptidylprolyl isomerase, with EC number 5.2.1.8 Full crystallographic information is available from OCA.

Reference

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

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