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Science 18 May 1990:
Vol. 248. no. 4957, pp. 863 - 866
DOI: 10.1126/science.1693013
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Articles
Science, Vol 248, Issue 4957, 863-866
Copyright © 1990 by American Association for the Advancement of Science
Inhibition of FKBP rotamase activity by immunosuppressant FK506: twisted amide surrogate
MK Rosen,
RF Standaert,
A Galat,
M Nakatsuka,
and
SL Schreiber
Department of Chemistry, Harvard University, Cambridge, MA 02138.
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 alpha-keto amid of FK506 serves as a surrogate for the twisted amide of a bound peptide substrate.
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