Three-dimensional structure and actions of immunosuppressants and their immunophilins

W. Braun, J. Kallen, V. Mikol, M. D. Walkinshaw, K. Wuthrich

Research output: Contribution to journalReview article

87 Scopus citations

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 (Gyp). 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.

Original languageEnglish (US)
Pages (from-to)63-72
Number of pages10
JournalFASEB Journal
Volume9
Issue number1
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

Keywords

  • FK506
  • FKBP
  • cyclophilin
  • cyclosporin A
  • rapamycin

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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