Exploiting protein symmetry to design light-controllable enzyme inhibitors

Angew Chem Int Ed Engl. 2014 Jan 7;53(2):595-8. doi: 10.1002/anie.201307207. Epub 2013 Nov 25.

Abstract

The activity of the metabolic branch-point enzyme PriA from Mycobacterium tuberculosis (mtPriA) can be controlled reversibly by light. Two-pronged inhibitors based on the dithienylethene scaffold were designed utilizing mtPriA's natural rotational symmetry. Switching from the flexible, ring-open to the rigid, ring-closed isomer reduces inhibition activity by one order of magnitude.

Keywords: biosynthesis; enzyme catalysis; enzyme inhibitors; molecular switches; photochromism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry*
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Histidine / biosynthesis
  • Isomerism
  • Light*
  • Molecular Dynamics Simulation
  • Mycobacterium tuberculosis / enzymology*
  • Photochemistry
  • Protein Binding
  • Protein Structure, Secondary
  • Tryptophan / biosynthesis

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Histidine
  • Tryptophan