Inhibition of bacterial RNA polymerase by streptolydigin: stabilization of a straight-bridge-helix active-center conformation.
We define the target, mechanism, and structural basis of inhibition of bacterial RNA polymerase (RNAP) by the tetramic acid antibiotic streptolydigin (Stl). Stl binds to a site adjacent to but not overlapping the RNAP active center and stabilizes an RNAP-active-center conformational state with a straight-bridge helix. The results provide direct support for the proposals that alternative straight-bridge-helix and bent-bridge-helix RNAP-active-center conformations exist and that cycling between straight-bridge-helix and bent-bridge-helix RNAP-active-center conformations is required for RNAP function. The results set bounds on models for RNAP function and suggest strategies for design of novel antibacterial agents.
Tuske
Steven
S
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
Sarafianos
Stefan G
SG
Wang
Xinyue
X
Hudson
Brian
B
Sineva
Elena
E
Mukhopadhyay
Jayanta
J
Birktoft
Jens J
JJ
Leroy
Olivier
O
Ismail
Sajida
S
Clark
Arthur D
AD
Dharia
Chhaya
C
Napoli
Andrew
A
Laptenko
Oleg
O
Lee
Jookyung
J
Borukhov
Sergei
S
Ebright
Richard H
RH
Arnold
Eddy
E
D000617:Aminoglycosides / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000201:enzymology* / Q000235:genetics*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D008958:Models, Molecular; D015394:Molecular Structure; D017433:Protein Structure, Secondary / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis*
D000617:Aminoglycosides; D012333:RNA, Messenger; C100307:streptolydigin; D012321:DNA-Directed RNA Polymerases