Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains.
Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains.
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DOI：
10.1021/cb4003283
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发表时间：
2013-11-15
影响因子：
4
通讯作者：
Schoenbrunn, Ernst
中科院分区：
文献类型：
--
作者：
Martin, Mathew P.;Olesen, Sanne H.;Georg, Gunda I.;Schoenbrunn, Ernst
含溴结构域蛋白被认为是非典型激酶，但其与激酶抑制剂相互作用的潜力尚不清楚。Dinaciclib是一种有效的细胞周期蛋白依赖性激酶（CDK）抑制剂，最近进入了治疗白血病的III期临床试验。我们以1.7 μ m的分辨率测定了dinaciclib与CDK 2复合物的晶体结构，揭示了ATP位点中复杂的结合相互作用网络，这解释了这种抑制剂的非凡效力和选择性。值得注意的是，dinaciclib还与布罗莫结构域睾丸特异性蛋白BRDT的乙酰赖氨酸识别位点相互作用，BRDT是布罗莫结构域BET家族的成员。dinaciclib与BRDT在2.0 μ M分辨率下的结合模式表明，一般激酶抑制剂（“铰链结合剂”）具有以前未认识到的作为溴结构域蛋白质-蛋白质抑制剂的潜力。这些发现可能为利用激酶抑制剂的巨大化学空间设计下一代溴结构域抑制剂提供新的结构框架。
Bromodomain-containing proteins are considered atypical kinases, but their potential to interact with kinase inhibitors is unknown. Dinaciclib is a potent inhibitor of cyclin-dependent kinases (CDKs) which recently advanced to Phase III clinical trials for the treatment of leukemia. We determined the crystal structure of dinaciclib in complex with CDK2 at 1.7 Å resolution, revealing an elaborate network of binding interactions in the ATP site which explains the extraordinary potency and selectivity of this inhibitor. Remarkably, dinaciclib also interacted with the acetyl-lysine recognition site of the bromodomain testis-specific protein BRDT, a member of the BET family of bromodomains. The binding mode of dinaciclib to BRDT at 2.0 Å resolution suggests that general kinase inhibitors (“hinge binders”) possess a previously unrecognized potential to act as protein-protein inhibitors of bromodomains. The findings may provide a new structural framework for the design of next-generation bromodomain inhibitors using the vast chemical space of kinase inhibitors.
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影响因子：
64.5
作者：
Matzuk MM;McKeown MR;Filippakopoulos P;Li Q;Ma L;Agno JE;Lemieux ME;Picaud S;Yu RN;Qi J;Knapp S;Bradner JE
通讯作者：
Bradner JE
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
7.3
作者：
Bamborough, Paul;Diallo, Hawa;Chung, Chun-wa
通讯作者：
Chung, Chun-wa