| 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 PubMed
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.
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
- ↑ Liu TC, Huang CJ, Chu YC, Wei CC, Chou CC, Chou MY, Chou CK, Yang JJ. Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Biochem Biophys Res Commun. 2000 Aug 11;274(3):811-6. PMID:10924358 doi:http://dx.doi.org/10.1006/bbrc.2000.3236
- ↑ Gotoh I, Adachi M, Nishida E. Identification and characterization of a novel MAP kinase kinase kinase, MLTK. J Biol Chem. 2001 Feb 9;276(6):4276-86. Epub 2000 Oct 19. PMID:11042189 doi:http://dx.doi.org/10.1074/jbc.M008595200
- ↑ Gross EA, Callow MG, Waldbaum L, Thomas S, Ruggieri R. MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. J Biol Chem. 2002 Apr 19;277(16):13873-82. Epub 2002 Feb 8. PMID:11836244 doi:http://dx.doi.org/10.1074/jbc.M111994200
- ↑ Cho YY, Bode AM, Mizuno H, Choi BY, Choi HS, Dong Z. A novel role for mixed-lineage kinase-like mitogen-activated protein triple kinase alpha in neoplastic cell transformation and tumor development. Cancer Res. 2004 Jun 1;64(11):3855-64. PMID:15172994 doi:http://dx.doi.org/10.1158/0008-5472.CAN-04-0201
- ↑ Tosti E, Waldbaum L, Warshaw G, Gross EA, Ruggieri R. The stress kinase MRK contributes to regulation of DNA damage checkpoints through a p38gamma-independent pathway. J Biol Chem. 2004 Nov 12;279(46):47652-60. Epub 2004 Sep 1. PMID:15342622 doi:http://dx.doi.org/10.1074/jbc.M409961200
- ↑ Choi HS, Choi BY, Cho YY, Zhu F, Bode AM, Dong Z. Phosphorylation of Ser28 in histone H3 mediated by mixed lineage kinase-like mitogen-activated protein triple kinase alpha. J Biol Chem. 2005 Apr 8;280(14):13545-53. Epub 2005 Jan 31. PMID:15684425 doi:http://dx.doi.org/M410521200
- ↑ 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. Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib. ACS Chem Biol. 2016 Mar 31. PMID:26999302 doi:http://dx.doi.org/10.1021/acschembio.6b00043
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