title: Inhibition of bacterial RNA polymerase by streptolydigin: stabilization of a straight-bridge-helix active-center conformation.
abstract: 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.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Tuske
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
authors.forename: Xinyue
authors.initials: X
authors.lastname: Wang
authors.forename: Brian
authors.initials: B
authors.lastname: Hudson
authors.forename: Elena
authors.initials: E
authors.lastname: Sineva
authors.forename: Jayanta
authors.initials: J
authors.lastname: Mukhopadhyay
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Birktoft
authors.forename: Olivier
authors.initials: O
authors.lastname: Leroy
authors.forename: Sajida
authors.initials: S
authors.lastname: Ismail
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Clark
authors.forename: Chhaya
authors.initials: C
authors.lastname: Dharia
authors.forename: Andrew
authors.initials: A
authors.lastname: Napoli
authors.forename: Oleg
authors.initials: O
authors.lastname: Laptenko
authors.forename: Jookyung
authors.initials: J
authors.lastname: Lee
authors.forename: Sergei
authors.initials: S
authors.lastname: Borukhov
authors.forename: Richard H
authors.initials: RH
authors.lastname: Ebright
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
mesh_terms: 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*
chemical_list: D000617:Aminoglycosides; D012333:RNA, Messenger; C100307:streptolydigin; D012321:DNA-Directed RNA Polymerases