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An inhibitor 'hijacks' kinase regulation. Okuzumi et al. (p 484) investigated the mechanism by which the ATP-competitive Akt inhibitor A-443654 induces hyperphosphorylation of Akt regulatory sites. Using chemical genetic tools, the authors found that inhibitor binding, rather than pathway feedback, directly triggers Akt hyperphosphorylation (see also News and Views by Frye and Johnson on p 448). The cover shows Akt in contact with two regulatory kinases, PDK and mTORC2, and an analog of A-443654. Cover art by Erin Dewalt.
Identifying and increasing access to the highest quality chemical probes will ensure their prominent position in the biological and drug discovery toolboxes.
Small-molecule inhibitors can induce phosphorylation priming of AGC kinases. Priming by ATP binding pocket conformation, rather than intrinsic kinase activity, has significant implications for drug discovery and therapeutic efficacy.
Microorganisms are a major source of new therapeutics. However, the discovery and sustainable production of these compounds are often hampered owing to limited access to biosynthetic genes or products. Recent studies provide new approaches for targeting biosynthesis genes in the metagenome of complex microbial assemblages and for inducing the expression of otherwise silent biosynthesis genes.
A new methodology combining small molecules and phage-displayed peptides enables the isolation of chemically modified bicyclic peptides capable of high-affinity recognition of target proteins.
Westheimer's classical proposal that the decreased pKa of Lys115 in the active site of acetoacetate decarboxylase is the result of its unfavorable electrostatic juxtaposition with Lys116 has been evaluated by X-ray crystallography. The long-awaited structure reveals that Lys115 is positioned in a hydrophobic pocket that lowers its pKa.