6MQG

Crystal structure of KRAS V14I-GDP demonstrating open switch 1 conformation - Form 1

Summary for 6MQG

• Entry DOI: 10.2210/pdb6mqg/pdb
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: gtpase kras hydrolysis, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 19512.69

Authors

Bera, A.K.,Westover, K.D. (deposition date: 2018-10-09, release date: 2019-07-31, Last modification date: 2024-11-20)

Primary citation

Bera, A.K.,Lu, J.,Wales, T.E.,Gondi, S.,Gurbani, D.,Nelson, A.,Engen, J.R.,Westover, K.D.
Structural basis of the atypical activation mechanism of KRASV14I.
J.Biol.Chem., 294:13964-13972, 2019

PubMed Abstract: RAS regulation and signaling are largely accomplished by direct protein-protein interactions, making RAS protein dynamics a critical determinant of RAS function. Here, we report a crystal structure of GDP-bound KRAS, a mutated KRAS variant associated with the developmental RASopathy disorder Noonan syndrome (NS), at 1.5-1.6 Å resolution. The structure is notable for revealing a marked extension of switch 1 away from the G-domain and nucleotide-binding site of the KRAS protein. We found that this extension is associated with a loss of the magnesium ion and a tilt in the position of the guanine base because of the additional carbon introduced by the isoleucine substitution. Hydrogen-deuterium exchange MS analysis confirmed that this conformation occurs in solution, but also disclosed a difference in kinetics when compared with KRAS, another RAS mutant that displays a nearly identical conformation in previously reported crystal structures. This conformational change contributed to a high rate of guanine nucleotide-exchange factor (GEF)-dependent and -independent nucleotide exchange and to an increase in affinity for SOS Ras/Rac GEF 1 (SOS1), which appears to be the major mode of activation for this RAS variant. These results highlight a mechanistic connection between KRAS and KRAS that may have implications for the regulation of these variants and for the development of therapeutic strategies to manage KRAS variant-associated disorders.

PubMed: 31341022
DOI: 10.1074/jbc.RA119.009131

Experimental method

X-RAY DIFFRACTION (1.5 Å)