title: Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes.
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.
authors.affiliation: Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7260, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Huai
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Yudong
authors.initials: Y
authors.lastname: Liu
authors.forename: Yingdong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Angelo
authors.initials: A
authors.lastname: Mondragon
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.forename: Hengming
authors.initials: H
authors.lastname: Ke
mesh_terms: D019703:Calcineurin / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D021984:Cyclophilin A / Q000737:chemistry*; D016572:Cyclosporine / Q000737:chemistry*; D006801:Humans; D020104:Immunophilins / Q000737:chemistry; D007166:Immunosuppressive Agents / Q000737:chemistry; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D008958:Models, Molecular; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D055672:Static Electricity; D016559:Tacrolimus / Q000737:chemistry; D022021:Tacrolimus Binding Proteins / Q000737:chemistry
chemical_list: D007166:Immunosuppressive Agents; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; C048022:substrate adhesion molecules; D016572:Cyclosporine; D019703:Calcineurin; D021984:Cyclophilin A; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D016559:Tacrolimus