Structure-based identification of the binding site for the hemiasterlin analogue HTI-286 on tubulin

Biochemistry. 2005 Dec 6;44(48):15871-9. doi: 10.1021/bi051268b.

Abstract

A binding mode of HTI-286, a synthetic analogue of the peptidic antimitotic agent hemiasterlin, to tubulin is proposed. The binding mode was derived from iterative docking experiments directed at regions of the tubulin interdimer interface that are believed to be consistent with all current experimental data regarding the HTI-286/tubulin interaction. These data include (1) competitive inhibition of the tubulin binding of the Vinca alkaloids and other antimitotic agents, (2) proximity to stretches of amino acid residues identified in two separate photoaffinity-labeling experiments, (3) structure-activity relationships for HTI-286 and its analogues, (4) saturation transfer difference nuclear magnetic resonance (NMR) experiments, and (5) NMR transfer nuclear Overhauser effect spectroscopy (NOESY) experiments that potentially identify the bioactive conformation. The predicted binding mode thus affords a means to understand the mode of action of hemiasterlin, HTI-286, and other closely related molecules.

MeSH terms

  • Antimitotic Agents / chemistry
  • Binding Sites*
  • Binding, Competitive
  • Electron Spin Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism*
  • Structure-Activity Relationship
  • Tubulin / chemistry
  • Tubulin / metabolism*

Substances

  • Antimitotic Agents
  • HTI-286
  • Oligopeptides
  • Tubulin