1qnh
From Proteopedia
(New page: 200px<br /><applet load="1qnh" size="450" color="white" frame="true" align="right" spinBox="true" caption="1qnh, resolution 2.1Å" /> '''PLASMODIUM FALCIPARUM...) |
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| - | [[Image:1qnh.jpg|left|200px]]<br /><applet load="1qnh" size=" | + | [[Image:1qnh.jpg|left|200px]]<br /><applet load="1qnh" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1qnh, resolution 2.1Å" /> | caption="1qnh, resolution 2.1Å" /> | ||
'''PLASMODIUM FALCIPARUM CYCLOPHILIN (DOUBLE MUTANT) COMPLEXED WITH CYCLOSPORIN A'''<br /> | '''PLASMODIUM FALCIPARUM CYCLOPHILIN (DOUBLE MUTANT) COMPLEXED WITH CYCLOSPORIN A'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Cyclosporin A (CsA) is a potent anti-malarial compound in vitro and in | + | 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== | ==About this Structure== | ||
| - | 1QNH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] and [http://en.wikipedia.org/wiki/Tolypocladium_inflatum Tolypocladium inflatum]. Active as [http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] Full crystallographic information is available from [http:// | + | 1QNH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] and [http://en.wikipedia.org/wiki/Tolypocladium_inflatum Tolypocladium inflatum]. Active as [http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QNH OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Tolypocladium inflatum]] | [[Category: Tolypocladium inflatum]] | ||
| - | [[Category: Hall, D | + | [[Category: Hall, D R.]] |
| - | [[Category: Hunter, W | + | [[Category: Hunter, W N.]] |
| - | [[Category: Peterson, M | + | [[Category: Peterson, M R.]] |
[[Category: cyclophilin a]] | [[Category: cyclophilin a]] | ||
[[Category: cyclosporin a]] | [[Category: cyclosporin a]] | ||
[[Category: peptidyl cis-trans isomerase]] | [[Category: peptidyl cis-trans isomerase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:41:44 2008'' |
Revision as of 12:41, 21 February 2008
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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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