5HES

Human leucine zipper- and sterile alpha motif-containing kinase (ZAK, MLT, HCCS-4, MRK, AZK, MLTK) in complex with vemurafenib

Summary for 5HES

• Entry DOI: 10.2210/pdb5hes/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase MLT, N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: kinase, complex, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q9NYL2
• Total number of polymer chains: 2
• Total formula weight: 71568.58

Authors

Mathea, S.,Salah, E.,Abdul Azeez, K.R.,Tallant, C.,Szklarz, M.,Chaikuad, A.,Shrestha, B.,Sorrell, F.J.,Elkins, J.M.,Shrestha, L.,Burgess-Brown, N.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S. (deposition date: 2016-01-06, release date: 2016-03-30, Last modification date: 2024-10-23)

Primary citation

Mathea, S.,Abdul Azeez, K.R.,Salah, E.,Tallant, C.,Wolfreys, F.,Konietzny, R.,Fischer, R.,Lou, H.J.,Brennan, P.E.,Schnapp, G.,Pautsch, A.,Kessler, B.M.,Turk, B.E.,Knapp, S.
Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib.
Acs Chem.Biol., 11:1595-1602, 2016

PubMed 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.

PubMed: 26999302
DOI: 10.1021/acschembio.6b00043

Experimental method

X-RAY DIFFRACTION (2.14 Å)