Combinatory Structural Biology of NRAS Q61 Melanomagenic Mutants

Using functional knock-in mice models, NRAS Q61 mutants display unique melanomagenicity properties, which are recapitulated in human mutational frequencies observed in melanoma. In particular, frequently observed melanoma mutants (NRAS Q61R and Q61K) promote tumor growth, while rare melanoma mutants (NRAS G12D, G13D, G13R, Q61L, Q61H, and Q61P) had lower tendency to cause spontaneous melanoma formation. 7,8 However, the molecular understanding for NRAS Q61 melanomagenicity is still unclear. RAS is an extremely dynamic system and because of this only 1 structural biology approach is inadequate to interrogate the molecular consequence of NRAS Q61 melanomagenicty. In order to address this question, we use a combinatory structural biological approach to identify populated conformers in the solution state and characterize variations in biochemical properties, as well as nuclear magnetic resonance (NMR) spectroscopic and computational studies.