TY - JOUR
T1 - Inhibition of FKBP rotamase activity by immunosuppressant FK506
T2 - Twisted amide surrogate
AU - Rosen, Michael K.
AU - Standaert, Robert F.
AU - Galat, Andrzej
AU - Nakatsuka, Masashi
AU - Schreiber, Stuart L.
PY - 1990
Y1 - 1990
N2 - 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.
AB - 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.
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U2 - 10.1126/science.1693013
DO - 10.1126/science.1693013
M3 - Article
C2 - 1693013
AN - SCOPUS:0025302066
SN - 0036-8075
VL - 248
SP - 863
EP - 866
JO - Science
JF - Science
IS - 4957
ER -