biostudies-literatureJohnson CWNSFLandry Family Cancer ConsortiumAmerican Cancer SocietyNCINIDDK NIH HHSNCI NIH HHS1538-1550.e7https://www.ebi.ac.uk/biostudies/studies/S-EPMC6709685biostudies-literatureUnknown28(6)Ras GTPases are mutated at codons 12, 13, and 61, with different frequencies in KRas, HRas, and NRas and in a cancer-specific manner. The G13D mutant appears in 25% of KRas-driven colorectal cancers, while observed only rarely in HRas or NRas. Structures of Ras G13D in the three isoforms show an open active site, with adjustments to the D13 backbone torsion angles and with disconnected switch regions. KRas G13D has unique features that destabilize the nucleotide-binding pocket. In KRas G13D bound to GDP, A59 is placed in the Mg²⁺ binding site, as in the HRas-SOS complex. Structure and biochemistry are consistent with an intermediate level of KRas G13D bound to GTP, relative to wild-type and KRas G12D, observed in genetically engineered mouse models. The results explain in part tCell reportsIsoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D.PMC6709685MRI-1228897R01CA232372R01CA195744130428-PF-17-066-01-TBGR01 CA195744MCB-1244203R01 CA232372P30 DK034854MCB-1517295K08 CA218420Mattos CDischinger PJohnson CWParker JGraveel CLin YJPavlopoulos SAguirre AJSteensma MHaigis KMReid DfalseIsoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D.Ras GTPases are mutated at codons 12, 13, and 61, with different frequencies in KRas, HRas, and NRas and in a cancer-specific manner. The G13D mutant appears in 25% of KRas-driven colorectal cancers, while observed only rarely in HRas or NRas. Structures of Ras G13D in the three isoforms show an open active site, with adjustments to the D13 backbone torsion angles and with disconnected switch regions. KRas G13D has unique features that destabilize the nucleotide-binding pocket. In KRas G13D bound to GDP, A59 is placed in the Mg²⁺ binding site, as in the HRas-SOS complex. Structure and biochemistry are consistent with an intermediate level of KRas G13D bound to GTP, relative to wild-type and KRas G12D, observed in genetically engineered mouse models. The results explain in part t2019-01-01T00:00:00Z2019 Aug2026-04-30T23:56:17.551Z2019-08-31T07:07:33ZS-EPMC67096853139056710.1016/j.celrep.2019.07.026