Structural and functional analysis of cyclin D1 reveals p27 and substrate inhibitor binding requirements.
Structural and functional analysis of cyclin D1 reveals p27 and substrate inhibitor binding requirements.
复制标题
DOI：
10.1021/cb1001262
复制
发表时间：
2010-12-17
影响因子：
4
通讯作者：
McInnes, Campbell
中科院分区：
文献类型：
--
作者：
Liu, Shu;Bolger, Joshua K.;Kirkland, Lindsay O.;Premnath, Padmavathy N.;McInnes, Campbell
在抗肿瘤药物开发中，通过细胞周期蛋白正调控亚单位上的底物募集位点提供了一种抑制细胞周期蛋白依赖性激酶的替代策略。关键的CDK底物，如Rb和E2F家族，在磷酸化之前必须经历周期蛋白沟槽结合，因此这种相互作用的抑制剂也可以阻断底物特异性激酶的活性。这种方法提供了产生高选择性和细胞周期特异性的CDK抑制剂的潜力，并减少了通过CDK7和9介导的转录抑制，这是ATP竞争化合物经常观察到的。虽然已经报道了CDK2/Cyclin A，E底物的高效多肽和小分子抑制剂的招募，但关于CDK4/Cyclin D1复合体的Cyclin槽结合的抑制剂的决定因素的信息很少。CDK4/Cyclin D是一种有效的抗癌药物靶点，在基于细胞周期阻断的新疗法的开发中继续被广泛追求。因此，我们研究了多肽与其周期蛋白沟槽结合的结构基础，并研究了有助于抑制剂效力和选择性的特征。合成了pRb磷酸化CDK4/细胞周期蛋白D的多肽抑制剂，并与CDK4/细胞周期蛋白D形成了晶体结构的络合物。基于已有的结构信息，对细胞周期蛋白A2和细胞周期蛋白D1的细胞周期蛋白沟槽进行了比较，并提供了对多肽结合的决定因素以及差异结合和抑制的基础的见解。此外，为了模拟CDKI p27KIP1与细胞周期蛋白D1的相互作用，已经产生了一个复杂的结构。这些信息已经被用来阐明CDK4的内源性抑制作用，也被用来确定Cyclin D1的独特方面，这些方面可以被用来设计基于Cyclin凹槽的CDK抑制剂。为了探索与细胞周期蛋白D1槽结合的构效关系，人们已经合成了多肽和非多肽化合物，到目前为止还没有系统地进行过研究。总的来说，这些数据为如何开发化合物提供了新的见解，这些化合物可以作为化学生物学探针来确定CDK抑制的细胞和抗肿瘤效果。此外，这些化合物将作为结构指导努力的模板，以开发基于选择性抑制CDK4/Cyclin D活性的潜在疗法。
An alternative strategy for inhibition of the cyclin dependent kinases in anti-tumor drug discovery is afforded through the substrate recruitment site on the cyclin positive regulatory subunit. Critical CDK substrates such as the Rb and E2F families must undergo cyclin groove binding before phosphorylation and hence inhibitors of this interaction also block substrate specific kinase activity. This approach offers the potential of generating highly selective and cell cycle specific CDK inhibitors and to reduce the inhibition of transcription mediated through CDK7 and 9, commonly observed with ATP competitive compounds. While highly potent peptide and small molecule inhibitors of CDK2/cyclin A, E substrate recruitment have been reported, little information has been generated on the determinants of inhibitor binding to the cyclin groove of the CDK4/cyclin D1 complex. CDK4/cyclin D is a validated anti-cancer drug target and continues to be widely pursued in the development of new therapeutics based on cell cycle blockade. We have therefore investigated the structural basis for peptide binding to its cyclin groove and have examined the features contributing to potency and selectivity of inhibitors. Peptidic inhibitors of CDK4/cyclin D of pRb phosphorylation have been synthesized, and their complexes with CDK4/cyclin D1 crystal structures have been generated. Based on available structural information, comparisons of the cyclin grooves of cyclin A2 and D1 are presented and provide insights into the determinants for peptide binding and the basis for differential binding and inhibition. In addition, a complex structure has been generated in order to model the interactions of the CDKI, p27KIP1, with cyclin D1. This information has been used shed light onto the endogenous inhibition of CDK4 and also to identify unique aspects of cyclin D1 and which can be exploited in the design of cyclin groove based CDK inhibitors. Peptidic and non-peptidic compounds have been synthesized in order to explore structure-activity relationship for binding to the cyclin D1 groove which to date has not been carried out in a systematic fashion. Collectively, the data presented provides new insights into how compounds can be developed that function as chemical biology probes to determine the cellular and anti-tumor effects of CDK inhibition. Furthermore, such compounds will serve as templates for structure-guided efforts to develop potential therapeutics based on selective inhibition of CDK4/cyclin D activity.
登录
查看更多内容
影响因子：
5.3
作者：
Ray, Arpita;James, Melissa K.;Blain, Stacy W.
通讯作者：
Blain, Stacy W.
影响因子：
11.2
作者：
Baughn, Linda B.;Di Liberto, Maurizio;Chen-Kiang, Selina
通讯作者：
Chen-Kiang, Selina
DOI：
10.2174/1568011033353506
发表时间：
2003-01-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
McInnes, Campbell;Andrews, Martin J. I.;Fischer, Peter M.
通讯作者：
Fischer, Peter M.
DOI：
10.1034/j.1399-3011.2002.21014.x
发表时间：
2002-11-01
期刊：
JOURNAL OF PEPTIDE RESEARCH
影响因子：
--
作者：
Zheleva, DI;McInnes, C;Lane, DP
通讯作者：
Lane, DP
影响因子：
3.2
作者：
Andrews, MJI;McInnes, C;Fischer, PM
通讯作者：
Fischer, PM