Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib
| Autor: | Stefan Knapp, Benjamin E. Turk, Finn Wolfreys, Rebecca Konietzny, Kamal R. Abdul Azeez, Gisela Schnapp, Eidarus Salah, Paul Brennan, Hua Jane Lou, Roman Fischer, Alexander Pautsch, Cynthia Tallant, S. Mathea, Benedikt M. Kessler |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Proto-Oncogene Proteins B-raf Indoles Calorimetry Crystallography X-Ray Biochemistry Article 03 medical and health sciences Adenosine Triphosphate medicine Humans Phosphorylation Vemurafenib Protein kinase A Peptide library Protein Kinase Inhibitors Genetics Leucine Zippers Sulfonamides MAP kinase kinase kinase Molecular Structure Kinase Chemistry General Medicine MAP Kinase Kinase Kinases Phosphoproteins 3. Good health 030104 developmental biology Drug Design Cancer research Molecular Medicine Oligopeptides Protein Kinases medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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