Stuck in the On Position

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Science  05 Jun 2009:
Vol. 324, Issue 5932, pp. 1243
DOI: 10.1126/science.324_1243a

Protein kinases are of course central components of many signaling pathways in cells. Cascades of kinases, in which the first kinase in a series modifies the second and enhances its enzyme activity, are not uncommon, and BRAF sits in a pathway that begins with a membrane-bound receptor tyrosine kinase and ends with the movement of the extracellular signal-regulated kinase into the nucleus. The special interest in BRAF arises from the frequent association of a mutation (V600E) of a valine to a glutamate with malignant melanoma. Xie et al. describe kinetic and structural studies of the interaction of wild-type and mutated forms of BRAF with kinase inhibitors built on a ruthenium (fuschia above) half-sandwich scaffold. They provide a structure-based explanation for the higher potency of one such inhibitor (CS292) for the V600E mutant versus the wild-type enzyme and use this information to design a more specific and more potent derivative. They also explain how the substitution of a glutamate electrostatically mimics the normal, activating phosphorylation of nearby serine and threonine residues, but with the critical distinction that activation in the BRAF mutant is irreversible.


Biochemistry 48, 10.1021/bi802067u (2009).

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