Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib.
Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib.
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DOI：
10.1021/acschembio.6b00043
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发表时间：
2016-06-17
影响因子：
4
通讯作者：
Knapp S
中科院分区：
文献类型：
--
作者：
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
混合谱系激酶 ZAK 是介导细胞存活和炎症反应的 MAPK 通路的关键调节因子。 ZAK 是多种临床批准的激酶抑制剂的靶点，据报道，抑制 ZAK 可以预防阿霉素诱发的心肌病。另一方面，ZAK 的非故意靶向与严重的副作用有关，例如皮肤鳞状细胞癌的发展。因此，ZAK 的特异性抑制剂以及缺乏针对 ZAK 的脱靶活性的抗癌药物都可能提供治疗益处。在这里，我们报道了 ZAK 与 B-RAF 抑制剂维莫非尼 (vemurafenib) 复合物的第一个晶体结构。共晶结构显示出许多 ZAK 特异性特征，包括高度扭曲的 P 环构象，可实现合理的抑制剂设计。位置扫描肽库分析揭示了 ZAK 激酶独特的底物特异性，包括相对于磷酸受体位点在位置 -1 和 +2 处对组氨酸残基的前所未有的偏好。此外，我们筛选了临床激酶抑制剂库，识别出几种有效抑制 ZAK 的抑制剂，证明当前使用的抗癌药物通常会误定位该激酶。
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 co-crystal 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.
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影响因子：
14.8
作者：
Chaikuad A;Tacconi EM;Zimmer J;Liang Y;Gray NS;Tarsounas M;Knapp S
通讯作者：
Knapp S
影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
16.6
作者：
Liu, Jinfeng;McCleland, Mark;Stawiski, Eric W.;Gnad, Florian;Mayba, Oleg;Haverty, Peter M.;Durinck, Steffen;Chen, Ying-Jiun;Klijn, Christiaan;Jhunjhunwala, Suchit;Lawrence, Michael;Liu, Hanbin;Wan, Yinan;Chopra, Vivek;Yaylaoglu, Murat B.;Yuan, Wenlin;Ha, Connie;Gilbert, Houston N.;Reeder, Jens;Pau, Gregoire;Stinson, Jeremy;Stern, Howard M.;Manning, Gerard;Wu, Thomas D.;Neve, Richard M.;de Sauvage, Frederic J.;Modrusan, Zora;Seshagiri, Somasekar;Firestein, Ron;Zhang, Zemin
通讯作者：
Zhang, Zemin
影响因子：
--
作者：
Fedorov O;Huber K;Eisenreich A;Filippakopoulos P;King O;Bullock AN;Szklarczyk D;Jensen LJ;Fabbro D;Trappe J;Rauch U;Bracher F;Knapp S
通讯作者：
Knapp S
影响因子：
4.3
作者：
Hsieh, You-Liang;Tsai, Ying-Lan;Huang, Chih-Yang
通讯作者：
Huang, Chih-Yang