Inhibition of FKBP rotamase activity by immunosuppressant FK506: Twisted amide surrogate

Michael K. Rosen, Robert F. Standaert, Andrzej Galat, Masashi Nakatsuka, Stuart L. Schreiber

Research output: Contribution to journalArticlepeer-review

184 Scopus citations


The immunosuppressive agents cyclosporin A and FK506 inhibit the transcription of early T cell activation genes. The binding proteins for cyclosporin A and FK506, cyclophilin and FKBP, respectively, are peptidyl-prolyl-cis-trans isomerases, or rotamases. One proposed mechanism for rotamase catalysis by cyclophilin involves a tetrahedral adduct of an amide carbonyl and an enzyme-bound nucleophile. The potent FKBP rotamase inhibitor FK506 has a highly electrophilic carbonyl that is adjacent to an acyl-pipicolinyl (homoprolyl) amide bond. Such a functional group would be expected to form a stabilized, enzyme-bound tetrahedral adduct. Spectroscopic and chemical evidence reveals that the drug interacts noncovalently with its receptor, suggesting that the α-keto amide of FK506 serves as a surrogate for the twisted amide of a bound peptide substrate.

Original languageEnglish (US)
Pages (from-to)863-866
Number of pages4
Issue number4957
StatePublished - 1990

ASJC Scopus subject areas

  • General


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