K-Ras Isoform B (G12C, C51S, C80L, C118S mutant; human, recombinant)

K-Ras is a small GTPase and member of the RAS family of GTPases with roles in apoptosis, as well as cell proliferation, survival, and migration.^1,2 K-Ras is composed of a guanine nucleotide-binding domain containing an active site, an effector-binding domain, and an isoform-specific C-terminal hypervariable region, which varies by four amino acids between isoforms A and B.^1,3 The active site cycles between GDP-bound inactive and GTP-bound active states and is regulated by its associations with GTPase-activating proteins (GAPs) or guanine nucleotide exchange factors (GEFs).^3,4 K-Ras is ubiquitously expressed and is tethered to the intracellular side of cell membranes via farnesyl and palmitoyl lipidation.^1,5 The glycine-to-cysteine substitution at position 12 of mutant K-Ras (K-Ras^G12C) is constitutively activating and found in pancreatic, colon, and lung cancers.^6,2 K-Ras^G12C substitutions of serine, leucine, and serine for the native cysteine residues in positions 51, 80, and 118 (C51S, C80L, C118S), respectively, of the guanine nucleotide-binding domain have minimal effects on protein structure, therefore, this tetramutated protein has been used to improve labeling of Cys¹² for protein crystallography and to reduce off-target inhibitor ligation and prevent cysteine-based reactions in kinetic assays.^7,8,9 Cayman’s K-Ras Isoform B (G12C, C51S, C80L, C118S mutant; human, recombinant) protein can be used for ELISA, enzyme activity assay, protein crystallography, and Western blot applications.

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1. Nussinov, R., Tsai, C.-J., Chakrabarti, M., et al. A new view of Ras isoforms in cancers. Cancer Res. 76(1), 18-23 (2016).

2. Padavano, J., Henkhaus, R.S., Chen, J., et al. Mutant K^-RAS promotes invasion and metastasis in pancreatic cancer through GTPase signaling pathways. Cancer Growth Metastasis 8 (Suppl 1), 95-113 (2015).

3. Hillig, R.C., Sautier, B., Schroeder, J., et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc. Natl. Acad. Sci. USA 116(7), 2551-2560 (2019).

4. Sermon, B.A., Eccleston, J.F., Skinner, R.H., et al. Mechanism of inhibition by arachidonic acid of the catalytic activity of ras GTPase-activating proteins. The Journal of Biological Chemisty 271(3), 1566-1572 (1996).

5. Salim, A.A., Tan, L., Huang, X.-C., et al. Oligomycins as inhibitors of K-Ras plasma membrane localisation. Org. Biomol. Chem. 14(2), 711-715 (2016).

6. Hallin, J., Engstrom, L.D., Hargis, L., et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10(1), 54-71 (2020).

7. Ostrem, J.M., Peters, U., Sos, M.L., et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503(7477), 548-551 (2013).

8. Zhang, Z., Guiley, K.Z., and Shokat, K.M. Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S). Nat. Chem. Biol. 18(11), 1177-1183 (2022).

9. Huynh, M.V., Parsonage, D., Forshaw, T.E., et al. Oncogenic KRAS G12C: Kinetic and redox characterization of covalent inhibition. The Journal of Biological Chemisty 298(8), 102186 (2022).