RAS Structural Biology

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Structure of wild-type KRAS4b in the GDP-bound form

Credit: Dhirendra Simanshu, NCI RAS Initiative

Recent studies from various laboratories have renewed our hope for the development of RAS-inhibitory molecules. Our group leads the structural biology efforts within the RAS Initiative. Our aim is to gain structural insights into wild-type and oncogenic mutants of KRAS in complex with various effectors/regulatory/partner proteins, which may identify novel binding pockets or interfaces amenable to attack with small molecules.

Our Progress

Our group has solved the first structure of KRAS4b protein in complex with PDEdelta, a protein that plays an important role in targeting KRAS4b to cellular membranes. This protein-protein complex structure shows every amino acid of full-length, fully processed KRAS protein for the first time.

Working to gain structural insights into KRAS mutations, we have solved the first structures of multiple oncogenic mutants of KRAS4b in the GTP-bound form. The GTP-bound forms of these mutants are the most common drivers of human cancers.

Our Projects

  • Solve structures of wild-type and oncogenic mutants of KRAS in the active state
  • Determine structures of KRAS complexes with various effectors and regulatory/trafficking proteins to aid structure-based drug design
  • Exploit structures for virtual compound screening followed by biochemical, biophysical and structural studies

Tools We Use

  • Nanoliter-scale protein crystallization system
  • Automated protein crystallization imaging system
  • Synchrotron beam line
  • In-house X-ray diffractometer
  • Isothermal titration calorimetry
  • Farnesylated and methylated KRAS4b

Collaborations

The RAS Structural Biology Group has collaborated with:

Nir London
Weizmann Institute of Science, Rehovot, Israel

Hans Robert Kalbitzer
University of Regensburg, Germany

Arul Chinnaiyan
Michigan Center for Translational Pathology, Ann Arbor, MI

Contact

Dr. Dhirendra Simanshu

Dr. Dhirendra Simanshu, Structural Biology Group Lead

For more information, contact the RAS Structural Biology Group team lead:

Dr. Dhirendra Simanshu
301-360-3438
dhirendra.simanshu@nih.gov

  • Updated: September 15, 2016