A competitive nucleotide binding inhibitor: in vitro characterization of Rab7 GTPase inhibition

ACS Chem Biol. 2012 Jun 15;7(6):1095-108. doi: 10.1021/cb3001099. Epub 2012 Apr 23.

Abstract

Mapping the functionality of GTPases through small molecule inhibitors represents an underexplored area in large part due to the lack of suitable compounds. Here we report on the small chemical molecule 2-(benzoylcarbamothioylamino)-5,5-dimethyl-4,7-dihydrothieno[2,3-c]pyran-3-carboxylic acid (PubChem CID 1067700) as an inhibitor of nucleotide binding by Ras-related GTPases. The mechanism of action of this pan-GTPase inhibitor was characterized in the context of the Rab7 GTPase as there are no known inhibitors of Rab GTPases. Bead-based flow cytometry established that CID 1067700 has significant inhibitory potency on Rab7 nucleotide binding with nanomolar inhibitor (K(i)) values and an inhibitory response of ≥97% for BODIPY-GTP and BODIPY-GDP binding. Other tested GTPases exhibited significantly lower responses. The compound behaves as a competitive inhibitor of Rab7 nucleotide binding based on both equilibrium binding and dissociation assays. Molecular docking analyses are compatible with CID 1067700 fitting into the nucleotide binding pocket of the GTP-conformer of Rab7. On the GDP-conformer, the molecule has greater solvent exposure and significantly less protein interaction relative to GDP, offering a molecular rationale for the experimental results. Structural features pertinent to CID 1067700 inhibitory activity have been identified through initial structure-activity analyses and identified a molecular scaffold that may serve in the generation of more selective probes for Rab7 and other GTPases. Taken together, our study has identified the first competitive GTPase inhibitor and demonstrated the potential utility of the compound for dissecting the enzymology of the Rab7 GTPase, as well as serving as a model for other small molecular weight GTPase inhibitors.

Publication types

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

MeSH terms

  • Binding, Competitive
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Guanosine Triphosphate / metabolism
  • Humans
  • Models, Molecular
  • Nucleotides / metabolism*
  • Protein Binding
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • rab GTP-Binding Proteins / antagonists & inhibitors*
  • rab GTP-Binding Proteins / metabolism
  • rab7 GTP-Binding Proteins

Substances

  • Carboxylic Acids
  • Enzyme Inhibitors
  • Nucleotides
  • Recombinant Proteins
  • Small Molecule Libraries
  • rab7 GTP-Binding Proteins
  • rab7 GTP-binding proteins, human
  • Guanosine Triphosphate
  • rab GTP-Binding Proteins