1M63

Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes

Summary for 1M63

• Entry DOI: 10.2210/pdb1m63/pdb
• Related: 1BCK 1C5F 1CSA 1CWA 1CWB 1CWC 1CWF 1CWH 1CWI 1CWJ 1CWK 1CWL 1CWM 1CWO 1CYA 1CYB 1CYN 1IKF 1MF8 1MIK 1QNG 1QNH 1XQ7 2ESL 2OJU 2POY 2RMA 2RMB 2RMC 2WFJ 2X2C 2X7K 2Z6W 3BO7 3CYS 3EOV
• Related PRD ID: PRD_000142
• Descriptor: SERINE/THREONINE PROTEIN PHOSPHATASE 2B CATALYTIC SUBUNIT, ALPHA ISOFORM, CALCINEURIN B SUBUNIT ISOFORM 1, PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A, ... (7 entities in total)
• Functional Keywords: hydrolase-isomerase-immunosuppressant complex, immunophilin, calcineurin, cyclosporin a, immunosuppressant, cyclophilin, hydrolase/isomerase/immunosuppressant
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cell membrane : Q08209; Cytoplasm, cytosol : P63098; Cytoplasm : P62937
• Total number of polymer chains: 8
• Total formula weight: 163213.10

Authors

Huai, Q.,Kim, H.-Y.,Liu, Y.,Zhao, Y.,Mondragon, A.,Liu, J.O.,Ke, H. (deposition date: 2002-07-12, release date: 2002-09-25, Last modification date: 2024-04-03)

Primary citation

Huai, Q.,Kim, H.-Y.,Liu, Y.,Zhao, Y.,Mondragon, A.,Liu, J.O.,Ke, H.
Crystal Structure of Calcineurin-Cyclophilin-Cyclosporin Shows Common But Distinct Recognition of Immunophilin-Drug Complexes
Proc.Natl.Acad.Sci.USA, 99:12037-, 2002

PubMed Abstract: Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, is the common target for two immunophilin-immunosuppressant complexes, cyclophilin A-cyclosporin A (CyPA-CsA) and FKBP-FK506. How the two structurally distinct immunophilin-drug complexes bind the same target has remained unknown. We report the crystal structure of calcineurin (CN) in complex with CyPA-CsA at 2.8-A resolution. The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN, where the complex of FK506 and its binding protein FKBP also binds. While the majority of the CN residues involved in the binding are common for both immunophilin-immunosuppressant complexes, a significant number of the residues are distinct. Unlike FKBP-FK506, CyPA-CsA interacts with Arg-122 at the active site of CN, implying direct involvement of CyPA-CsA in the regulation of CN catalysis. The simultaneous interaction of CyPA with both the composite surface and the active site of CN suggests that the composite surface may serve as a substrate recognition site responsible for the narrow substrate specificity of CN. The comparison of CyPA-CsA-CN with FKBP-FK506-CN significantly contributes to understanding the molecular basis of regulation of CN activity by the immunophilin-immunosuppressant.

PubMed: 12218175
DOI: 10.1073/PNAS.192206699

Experimental method

X-RAY DIFFRACTION (2.8 Å)