Abstract
The resistance of the human parasite Brugia malayi to the antiparasitic activity of cyclosporin A (CsA) may arise from the presence of cyclophilins with relatively low affinity for the drug. The structure of the complex of B. malayi cyclophilin (BmCYP-1) and CsA, with eight independent copies in the asymmetric unit, has been determined at a resolution of 2.7 A. The low affinity of BmCYP-1 for CsA arises from incomplete preorganization of the binding site so that the formation of a hydrogen bond between His132 of BmCYP-1 and N-methylleucine 9 of CsA is associated with a shift in the backbone of approximately 1 A in this region.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Binding Sites
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Brugia malayi / enzymology*
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Brugia malayi / genetics
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Crystallography, X-Ray / methods
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Cyclosporine / chemistry*
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Cyclosporine / metabolism
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Humans
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Hydrogen Bonding
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Models, Molecular
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Molecular Sequence Data
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Open Reading Frames
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Peptidylprolyl Isomerase / chemistry*
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Peptidylprolyl Isomerase / genetics
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Peptidylprolyl Isomerase / metabolism
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Protein Structure, Secondary
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
Substances
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Recombinant Proteins
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Cyclosporine
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Peptidylprolyl Isomerase