Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations.
Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations.
复制标题
DOI：
10.1038/s41598-017-07755-y
复制
发表时间：
2017-08-08
影响因子：
4.6
通讯作者：
Gileadi O
中科院分区：
文献类型：
--
作者：
Couñago RM;Allerston CK;Savitsky P;Azevedo H;Godoi PH;Wells CI;Mascarello A;de Souza Gama FH;Massirer KB;Zuercher WJ;Guimarães CRW;Gileadi O
人类基因组编码两种活性牛痘相关蛋白激酶（VRK），VRK 1和VRK 2。这些蛋白质与许多细胞过程有关，并与各种肿瘤有关。然而，理解VRK的细胞作用并确定其作为治疗干预靶点的潜在用途受到缺乏可以特异性调节细胞中这些激酶活性的工具化合物的限制。在这里，我们确定了BI-D1870，RSK激酶的二氢蝶啶抑制剂，作为一个有前途的起点，为发展化学探针靶向活性VRKs。我们解析了与BI-D1870结合的VRK 1和VRK 2以及与两种广谱抑制剂结合的VRK 1的共晶体结构。这些结构揭示了两种VRK都可以采用P环折叠构象，其通过每种蛋白质上的不同机制来稳定。基于这些结构，我们建议对二氢蝶啶支架进行修饰，可以探索产生针对VRK 1和VRK 2的有效和特异性抑制剂。
The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2.
登录
查看更多内容
影响因子：
14.8
作者：
Arrowsmith CH;Audia JE;Austin C;Baell J;Bennett J;Blagg J;Bountra C;Brennan PE;Brown PJ;Bunnage ME;Buser-Doepner C;Campbell RM;Carter AJ;Cohen P;Copeland RA;Cravatt B;Dahlin JL;Dhanak D;Edwards AM;Frederiksen M;Frye SV;Gray N;Grimshaw CE;Hepworth D;Howe T;Huber KV;Jin J;Knapp S;Kotz JD;Kruger RG;Lowe D;Mader MM;Marsden B;Mueller-Fahrnow A;Müller S;O'Hagan RC;Overington JP;Owen DR;Rosenberg SH;Roth B;Ross R;Schapira M;Schreiber SL;Shoichet B;Sundström M;Superti-Furga G;Taunton J;Toledo-Sherman L;Walpole C;Walters MA;Willson TM;Workman P;Young RN;Zuercher WJ
通讯作者：
Zuercher WJ
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
DOI：
10.1073/pnas.0708800104
发表时间：
2007-12-18
影响因子：
11.1
作者：
Fedorov, Oleg;Marsden, Brian;Knapp, Stefan
通讯作者：
Knapp, Stefan
影响因子：
5.3
作者：
Kang, Tae-Hong;Park, Do-Young;Kim, Kyong-Tai
通讯作者：
Kim, Kyong-Tai
影响因子：
7.3
作者：
Bramson, HN;Corona, J;Kuyper, LF
通讯作者：
Kuyper, LF