Active site targeting of hedgehog precursor protein with phenylarsine oxide

Chembiochem. 2015 Jan 2;16(1):55-8. doi: 10.1002/cbic.201402421. Epub 2014 Nov 21.

Abstract

Hedgehog proteins, signaling molecules implicated in human embryo development and cancer, can be inhibited at the stage of autoprocessing by the trivalent arsenical phenyl arsine oxide (PhAs(III) ). The interaction (apparent Ki , 4 × 10(-7) M) is characterized by an optical binding assay and by NMR spectroscopy. PhAs(III) appears to be the first validated inhibitor of hedgehog autoprocessing, which is unique to hedgehog proteins and essential for biological activity.

Keywords: active-site probe; arsenic; autoprocessing; cholesterol; hedgehog.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arsenicals / chemistry*
  • Catalytic Domain
  • Cholesterol / chemistry*
  • Dose-Response Relationship, Drug
  • Drosophila melanogaster / chemistry
  • Drosophila melanogaster / metabolism
  • Gene Expression
  • Hedgehog Proteins / antagonists & inhibitors*
  • Hedgehog Proteins / chemistry
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Humans
  • Hydrolysis
  • Kinetics
  • Models, Molecular
  • Protein Binding
  • Protein Precursors / antagonists & inhibitors*
  • Protein Precursors / chemistry
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Recombinant Fusion Proteins / chemistry*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism

Substances

  • Arsenicals
  • Hedgehog Proteins
  • Protein Precursors
  • Recombinant Fusion Proteins
  • oxophenylarsine
  • Cholesterol