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ACS Chem Biol. 2016 Jun 17;11(6):1595-602. doi: 10.1021/acschembio.6b00043. Epub 2016 Mar 31.

Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib.

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Structural Genomics Consortium (SGC), Nuffield Department of Medicine, University of Oxford , Oxford, OX37DQ, United Kingdom.
Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford , Oxford, OX37FZ, United Kingdom.
Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut 06520, United States.
Lead Discovery and Optimisation Support, Boehringer Ingelheim Pharma GmbH & Co KG , Biberach, 88400, Germany.
Institute for Pharmaceutical Chemistry and Buchmann Institute for Molecular Life Sciences (BMLS), Johann Wolfgang Goethe University , Frankfurt am Main, 60438, Germany.


The mixed lineage kinase ZAK is a key regulator of the MAPK pathway mediating cell survival and inflammatory response. ZAK is targeted by several clinically approved kinase inhibitors, and inhibition of ZAK has been reported to protect from doxorubicin-induced cardiomyopathy. On the other hand, unintended targeting of ZAK has been linked to severe adverse effects such as the development of cutaneous squamous cell carcinoma. Therefore, both specific inhibitors of ZAK, as well as anticancer drugs lacking off-target activity against ZAK, may provide therapeutic benefit. Here, we report the first crystal structure of ZAK in complex with the B-RAF inhibitor vemurafenib. The cocrystal structure displayed a number of ZAK-specific features including a highly distorted P loop conformation enabling rational inhibitor design. Positional scanning peptide library analysis revealed a unique substrate specificity of the ZAK kinase including unprecedented preferences for histidine residues at positions -1 and +2 relative to the phosphoacceptor site. In addition, we screened a library of clinical kinase inhibitors identifying several inhibitors that potently inhibit ZAK, demonstrating that this kinase is commonly mistargeted by currently used anticancer drugs.

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