Susan K. Fetics

author keywords: allosteric site; allostery; HRAS; hydrolysis; KRAS; mutation; RAF; small GTPase

TL;DR: It is shown that closure of the allosteric site correlates with increased hydrolysis of GTP on HRAS in solution, and this behavior may be representative of a cluster of poorly understood mutations that occur in human tumors, which potentially cooperate with RAF complex formation to stabilize the GTP-bound state of RAS. (via Semantic Scholar)

MeSH headings : Allosteric Regulation; Catalytic Domain; Crystallography, X-Ray; Humans; Hydrogen Bonding; Molecular Dynamics Simulation; Mutation, Missense; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Quaternary; Protein Structure, Secondary; Proto-Oncogene Proteins c-raf / chemistry; Proto-Oncogene Proteins p21(ras) / chemistry; Proto-Oncogene Proteins p21(ras) / genetics

TL;DR: In addition to local perturbations on Ras, RasQ61L has substantial long-range effects on the Ras allosteric lobe and on Raf-RBD, which is essential for the activation of the Raf kinase domain through a currently unknown mechanism. (via Semantic Scholar)

author keywords: GTPase; Raf; calcium; intrinsic hydrolysis

MeSH headings : Acetates / pharmacology; Allosteric Regulation / drug effects; Allosteric Site; Biocatalysis / drug effects; Calcium / metabolism; Calcium Compounds / pharmacology; Catalytic Domain; Crystallography, X-Ray; Enzyme Stability / drug effects; Glutamine / metabolism; Hydrogen Bonding / drug effects; Hydrolysis / drug effects; Hydroxyl Radical / metabolism; Magnesium / metabolism; Models, Molecular; Protein Structure, Tertiary; Structure-Activity Relationship; ras Proteins / chemistry; ras Proteins / metabolism

TL;DR: This structure suggests a direct catalytic role for Q61 where it interacts with a water molecule that bridges one of the γ-phosphate oxygen atoms to the hydroxyl group of Y32 to stabilize the transition state of the hydrolysis reaction. (via Semantic Scholar)