1QNG

Plasmodium falciparum Cyclophilin complexed with Cyclosporin A

Summary for 1QNG

• Entry DOI: 10.2210/pdb1qng/pdb
• Related: 1BCK 1C5F 1CSA 1CWA 1CWB 1CWC 1CWF 1CWH 1CWI 1CWJ 1CWK 1CWL 1CWM 1CWO 1CYA 1CYB 1CYN 1IKF 1M63 1MF8 1MIK 1QNH 1XQ7 2ESL 2OJU 2POY 2RMA 2RMB 2RMC 2WFJ 2X2C 2X7K 2Z6W 3BO7 3CYS 3EOV
• Related PRD ID: PRD_000142
• Descriptor: PEPTIDYL-PROLYL CIS-TRANS ISOMERASE, CYCLOSPORIN A (3 entities in total)
• Functional Keywords: isomerase-immunosuppressant complex, cyclophilin-cyclosporin complex, cyclosporin a, immunosuppressant, cyclophilin, isomerase/immunosuppressant
• Biological source: PLASMODIUM FALCIPARUM; More
• Total number of polymer chains: 2
• Total formula weight: 20066.00

Authors

Peterson, M.R.,Hall, D.R.,Hunter, W.N. (deposition date: 1999-10-14, release date: 2000-10-13, Last modification date: 2023-12-13)

Primary citation

Peterson, M.R.,Hall, D.R.,Berriman, M.,Leonard, G.A.,Fairlamb, A.H.,Hunter, W.N.
The Three-Dimensional Structure of a Plasmodium Falciparum Cyclophilin in Complex with the Potent Anti-Malarial Cyclosporin A
J.Mol.Biol., 298:123-, 2000

PubMed Abstract: 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.

PubMed: 10756109
DOI: 10.1006/JMBI.2000.3633

Experimental method

X-RAY DIFFRACTION (2.1 Å)