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Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib

DOI: 10.1021/acschembio.6b00043 DOI Help

Authors: Sebastian Mathea (University of Oxford) , Kamal R. Abdul Azeez (University of Oxford) , Eidarus Salah (University of Oxford) , Cynthia Tallant (University of Oxford) , Finn Wolfreys (University of Oxford) , Rebecca Konietzny (University of Oxford) , Roman Fischer (University of Oxford) , Hua Jane Lou (University School of Medicine) , Paul E. Brennan (University of Oxford) , Gisela Schnapp (Boehringer Ingelheim Pharma GmbH & Co KG) , Alexander Pautsch (Boehringer Ingelheim Pharma GmbH & Co KG) , Benedikt M. Kessler (University of Oxford) , Benjamin E. Turk (University School of Medicine) , Stefan Knapp (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: March 2016

Abstract: 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.

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 06/04/2016 16:04

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