Trends in Biochemical Sciences
LetterAffinity of guanine nucleotide binding proteins for their ligands: facts and artefacts
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Drugging the undruggable: Advances in targeting KRAS signaling in solid tumors
2024, International Review of Cell and Molecular BiologyKRAS G12C in advanced NSCLC: Prevalence, co-mutations, and testing
2023, Lung CancerDesign, synthesis, and evaluation of 4(1H)-quinolinone and urea derivatives as KRAS<sup>G12C</sup> inhibitors with potent antitumor activity against KRAS-mutant non-small cell lung cancer
2022, European Journal of Medicinal ChemistryCitation Excerpt :However, until very recently, direct targeting of RAS mutations was considered ‘mission impossible’ for several decades, although various inhibitors have been developed based on RAS membrane localization [8] or the interaction between RAS and its regulators and downstream signaling including RasGEFs [9–11], RAF-MEK-ERK [12], PI3K-AKT-mTOR [13] and RalGEF-RAL-RalBP1 [14]. RAS mutants are difficult to target directly for two reasons: (1) The smooth surface of RAS protein resulting in no binding pockets suitable for inhibitor binding [15]; (2) The picomolar binding affinity of RAS to GTP/GDP making the identification of competitive inhibitors extremely difficult if not impossible [16,17]. Recent breakthroughs in the direct targeting of RAS are all rooted in the discovery of lead compounds by Shokat and coworkers, which can covalently bind to the cysteine residue in KRASG12C mutation [18].
Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families
2022, Journal of Molecular BiologyMutant-Specific Targeting of Ras G12C Activity by Covalently Reacting Small Molecules
2019, Cell Chemical BiologyCitation Excerpt :It was noticed quite early that Ras and related GTPases have a very high affinity for guanine nucleotides. In fact, this affinity is so high (Kd in the 10 μM range) that initial estimates were erroneous, partly owing to the fact that Ras proteins are isolated after expression in bacteria as stable 1:1 complexes with GDP (Goody et al., 1991). Accurate measurements of nucleotide affinities could only be made after methods for the generation of the relatively unstable nucleotide-free protein were developed (Feuerstein et al., 1987; John et al., 1990).
Conformational resolution of nucleotide cycling and effector interactions for multiple small GTPases determined in parallel
2019, Journal of Biological Chemistry