Crystallographic characterization of the ribosomal binding site and molecular mechanism of action of Hygromycin A

Nucleic Acids Res. 2015 Nov 16;43(20):10015-25. doi: 10.1093/nar/gkv975. Epub 2015 Oct 12.

Abstract

Hygromycin A (HygA) binds to the large ribosomal subunit and inhibits its peptidyl transferase (PT) activity. The presented structural and biochemical data indicate that HygA does not interfere with the initial binding of aminoacyl-tRNA to the A site, but prevents its subsequent adjustment such that it fails to act as a substrate in the PT reaction. Structurally we demonstrate that HygA binds within the peptidyl transferase center (PTC) and induces a unique conformation. Specifically in its ribosomal binding site HygA would overlap and clash with aminoacyl-A76 ribose moiety and, therefore, its primary mode of action involves sterically restricting access of the incoming aminoacyl-tRNA to the PTC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cinnamates / chemistry*
  • Cinnamates / metabolism
  • Cinnamates / pharmacology*
  • Crystallography, X-Ray
  • Hygromycin B / analogs & derivatives*
  • Hygromycin B / chemistry
  • Hygromycin B / metabolism
  • Hygromycin B / pharmacology
  • Models, Molecular
  • Peptidyl Transferases / chemistry
  • Peptidyl Transferases / drug effects
  • Protein Synthesis Inhibitors / chemistry*
  • Protein Synthesis Inhibitors / metabolism
  • Protein Synthesis Inhibitors / pharmacology*
  • RNA, Transfer, Amino Acyl / metabolism
  • Ribosome Subunits, Large, Bacterial / chemistry*
  • Ribosome Subunits, Large, Bacterial / drug effects*
  • Ribosome Subunits, Large, Bacterial / enzymology
  • Ribosome Subunits, Large, Bacterial / metabolism

Substances

  • Cinnamates
  • Protein Synthesis Inhibitors
  • RNA, Transfer, Amino Acyl
  • Hygromycin B
  • hygromycin A
  • Peptidyl Transferases