Three-dimensional structure and actions of immunosuppressants and their immunophilins

FASEB J. 1995 Jan;9(1):63-72. doi: 10.1096/fasebj.9.1.7529736.

Abstract

The use of the immunosuppressant drug cyclosporin A (CsA) as a biochemical tool to study the signal transduction pathway in T cells has led to the discovery of a first family of immunosuppressant-binding proteins or "immunophilins," the cyclophilins (Cyp). Another, chemically unrelated immunosuppressant molecule, FK506, was then found to be related to a second class of immunophilins, the FK506-binding proteins (FKBPs). This paper reviews the existing structural information on these immunophilins in the context of present knowledge of the biochemical mechanisms for immunosuppression. The formation of Cyp-CsA and FKBP-FK506 complexes, and the subsequent specific interaction of these complexes with the serine/threonine phosphatase calcineurin (CN), are key steps in the cascade of events that result in the desired immunosuppression. Knowledge of the conformation of the Cyp-CsA-CN and FKBP-FK506-CN ternary complexes is of significant biomedical interest, because mimics of the composite contact surfaces of, for example, Cyp-CsA or FKBP-FK506, could provide immunosuppressant drugs with improved pharmacological profiles.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Isomerases / chemistry
  • Amino Acid Isomerases / metabolism
  • Calcineurin
  • Calmodulin-Binding Proteins / antagonists & inhibitors
  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism
  • Cyclosporine / chemistry
  • Cyclosporine / metabolism
  • Cyclosporine / pharmacology
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Heat-Shock Proteins / chemistry
  • Heat-Shock Proteins / metabolism
  • Humans
  • Immunosuppressive Agents / chemistry*
  • Immunosuppressive Agents / metabolism
  • Immunosuppressive Agents / pharmacology*
  • Models, Molecular
  • Peptidylprolyl Isomerase
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Tacrolimus / chemistry
  • Tacrolimus / metabolism
  • Tacrolimus / pharmacology
  • Tacrolimus Binding Proteins

Substances

  • Calmodulin-Binding Proteins
  • Carrier Proteins
  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Immunosuppressive Agents
  • Cyclosporine
  • Calcineurin
  • Phosphoprotein Phosphatases
  • Amino Acid Isomerases
  • Tacrolimus Binding Proteins
  • Peptidylprolyl Isomerase
  • Tacrolimus