Letter
Affinity of guanine nucleotide binding proteins for their ligands: facts and artefacts

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    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].

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    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).

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