5V71

KRAS G12C in bound to quinazoline based switch II pocket (SWIIP) binder

Summary for 5V71

• Entry DOI: 10.2210/pdb5v71/pdb
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: kras, covalent inhibitor, quinazoline based, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• Total number of polymer chains: 6
• Total formula weight: 120672.54

Authors

Westover, K.,Lu, J. (deposition date: 2017-03-17, release date: 2017-08-23, Last modification date: 2024-11-06)

Primary citation

Lu, J.,Harrison, R.A.,Li, L.,Zeng, M.,Gondi, S.,Scott, D.,Gray, N.S.,Engen, J.R.,Westover, K.D.
KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry.
Structure, 25:1442-1448.e3, 2017

PubMed Abstract: KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders. We investigated the structural basis for differences in HDX MS using X-ray crystallography and discovered a new SIIP configuration in response to binding of a quinazoline chemotype. These results have implications for structure-guided drug design targeting the RAS SIIP.

PubMed: 28781083
DOI: 10.1016/j.str.2017.07.003

Experimental method

X-RAY DIFFRACTION (2.228 Å)