5hes
From Proteopedia
Human leucine zipper- and sterile alpha motif-containing kinase (ZAK, MLT, HCCS-4, MRK, AZK, MLTK) in complex with vemurafenib
Structural highlights
Function[MLTK_HUMAN] Stress-activated component of a protein kinase signal transduction cascade. Regulates the JNK and p38 pathways. Pro-apoptotic. Role in regulation of S and G2 cell cycle checkpoint by direct phosphorylation of CHEK2. Isoform 1, but not isoform 2, causes cell shrinkage and disruption of actin stress fibers. Isoform 1 may have role in neoplastic cell transformation and cancer development. Isoform 1, but not isoform 2, phosphorylates histone H3 at 'Ser-28'.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe 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. Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib.,Mathea S, Abdul Azeez KR, Salah E, Tallant C, Wolfreys F, Konietzny R, Fischer R, Lou HJ, Brennan PE, Schnapp G, Pautsch A, Kessler BM, Turk BE, Knapp S ACS Chem Biol. 2016 Mar 31. PMID:26999302[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Large Structures | Mitogen-activated protein kinase kinase kinase | Arrowsmith, C H | Azeez, K R.Abdul | Bountra, C | Burgess-Brown, N | Chaikuad, A | Delft, F von | Edwards, A M | Elkins, J M | Knapp, S | Mathea, S | Salah, E | Shrestha, B | Shrestha, L | Sorrell, F J | Szklarz, M | Tallant, C | Complex | Kinase | Transferase
