TY - JOUR
T1 - Structural mechanism of inhibition of the Rho transcription termination factor by the antibiotic bicyclomycin
AU - Skordalakes, Emmanuel
AU - Brogan, Andrew P.
AU - Park, Boon Saeng
AU - Kohn, Harold
AU - Berger, James M.
N1 - Funding Information:
We thank Dr. Y. Itoh and the Fujisawa Pharmaceutical Co., Ltd., Japan, for the gift of BCM. This work was supported by the National Institutes of Health grant GM37934 (H.K.) and by generous funding from the G. Harold and Leila Y. Mathers Charitable Foundation. The American Chemical Society Division of Medicinal Chemistry and Bristol-Myers Squibb are gratefully acknowledged for support of a predoctoral fellowship to A.P.B.
PY - 2005/1
Y1 - 2005/1
N2 - Rho is a hexameric RNA/DNA helicase/translocase that terminates transcription of select genes in bacteria. The naturally occurring antibiotic, bicyclomycin (BCM), acts as a noncompetitive inhibitor of ATP turnover to disrupt this process. We have determined three independent X-ray crystal structures of Rho complexed with BCM and two semisynthetic derivatives, 5a-(3-formylphenylsulfanyl)-dihydrobicyclomycin (FPDB) and 5a-formylbicyclomycin (FB) to 3.15, 3.05, and 3.15 Å resolution, respectively. The structures show that BCM and its derivatives are nonnucleotide inhibitors that interact with Rho at a pocket adjacent to the ATP and RNA binding sites in the C-terminal half of the protein. BCM association prevents ATP turnover by an unexpected mechanism, occluding the binding of the nucleophilic water molecule required for ATP hydrolysis. Our data explain why only certain elements of BCM have been amenable to modification and serve as a template for the design of new inhibitors.
AB - Rho is a hexameric RNA/DNA helicase/translocase that terminates transcription of select genes in bacteria. The naturally occurring antibiotic, bicyclomycin (BCM), acts as a noncompetitive inhibitor of ATP turnover to disrupt this process. We have determined three independent X-ray crystal structures of Rho complexed with BCM and two semisynthetic derivatives, 5a-(3-formylphenylsulfanyl)-dihydrobicyclomycin (FPDB) and 5a-formylbicyclomycin (FB) to 3.15, 3.05, and 3.15 Å resolution, respectively. The structures show that BCM and its derivatives are nonnucleotide inhibitors that interact with Rho at a pocket adjacent to the ATP and RNA binding sites in the C-terminal half of the protein. BCM association prevents ATP turnover by an unexpected mechanism, occluding the binding of the nucleophilic water molecule required for ATP hydrolysis. Our data explain why only certain elements of BCM have been amenable to modification and serve as a template for the design of new inhibitors.
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U2 - 10.1016/j.str.2004.10.013
DO - 10.1016/j.str.2004.10.013
M3 - Article
C2 - 15642265
AN - SCOPUS:11844255730
SN - 0969-2126
VL - 13
SP - 99
EP - 109
JO - Structure
JF - Structure
IS - 1
ER -