Abstract
RAS (KRAS, NRAS, and HRAS) proteins have widespread command of cellular circuitry and are high-priority drug targets in cancers and other diseases. Effectively targeting RAS proteins requires an exact understanding of their active, inactive, and druggable conformations, and the structural impact of mutations. Here we define an expanded classification of RAS conformations by clustering all 699 available human KRAS, NRAS, and HRAS structures in the Protein Data Bank (PDB) by the arrangement of their catalytic switch 1 (SW1) and switch 2 (SW2) loops. This enabled us to clearly define the geometry of closely related RAS conformations, many of which were not previously described. We determined the catalytic impact of the most common RAS mutations and identified several novel druggable RAS conformations. Our study expands the topography of characterized RAS conformations and will help inform future structure-guided RAS drug design.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
e-mail: Roland.dunbrack{at}fccc.edu