Background: Cyclophilin (CyP) is a ubiquitious intracellular protein that binds the immunosuppressive drug cyclosporin A (CsA). CyP-CsA forms a ternary complex with calcineurin and thereby inhibits T-cell activation. CyP also has enzymatic activity, catalyzing the cis-trans isomerization of peptidyl-prolyl amide bonds.
Results: We have determined the structure of human cyclophilin A (CyPA) complexed with CsA to 2.1 A resolution. We also report here the structure of CyPA complexed with an analog of CsA, CsA (MeBm2t1-CsA), which binds less well to CyPA, but has increased immunosuppressive activity. Comparison of these structures with previously determined structures of unligated CyPA and CyPA complexed with a candidate substrate for the isomerase activity, the dipeptide AlaPro, reveals that subtle conformational changes occur in both CsA and CyPA on complex formation.
Conclusions: MeBm2t1-CsA binds to CyPA in an essentially similar manner to CsA. The 100-fold weaker affinity of its binding may be attributable to the close contact between MeBmt1 and the active site residue Ala103 of CyPA, which causes small conformational changes in both protein and drug. One change, the slight movement of MeLeu6 in CsA relative to MeBm2t1-CsA, may be at least partially responsible for the higher affinity of the CyPA-MeBm2t1-CsA complex for calcineurin. Our comparison between CyPA-CsA and CyPA-AlaPro suggests that CsA is probably not an analog of the natural substrate, confirming that the catalytic activity of CyPA is not related to its role in immunosuppression either structurally or functionally.
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Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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Site | Modification | Modifier | Source | Reference |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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