Calcineurin (CN) is a Ca2+/calmodulin-dependent serine/threonine protein phosphatase and is involved in many physiological processes such as T-cell activation and cardiac hypertrophy. The crystal structures of CN and its complexes with FKBP12-FK506 and cyclophilin-cyclosporin showed that the two structurally unrelated immunophilins-immunosuppressants bind to a common composite surface made up of the residues from both catalytic subunit and regulatory subunit of CN. The recognition of the immunophilins and immuno suppressive drugs is achieved by common but few distinct CN residues. However, the binding pattern of FKBP12-FK506 such as hydrogen bonding is significantly different from that of CyPA-CsA. This common but distinct recognition may indicate capacity of the composition surface for binding of other inhibitory proteins. The recognition site and the active site are adjacent and form an "L" shaped cleft. This implies that the immunophilin recognition site may also serve as a recognition site to define the narrow substrate specificity of calcineurin. (C) 2003 Elsevier Inc. All rights reserved.