Identifying Small-Molecule Binding Sites for Epigenetic Proteins at Domain-Domain Interfaces.
Identifying Small-Molecule Binding Sites for Epigenetic Proteins at Domain-Domain Interfaces.
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DOI：
10.1002/cmdc.201800030
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发表时间：
2018-05-23
期刊：
影响因子：
3.4
通讯作者：
Brennan PE
中科院分区：
文献类型：
--
作者：
Bowkett D;Talon R;Tallant C;Schofield C;von Delft F;Knapp S;Bruton G;Brennan PE
表观遗传学是药物发现中一个快速发展的领域。特别令人感兴趣的是组蛋白翻译后修饰的作用，以及读、写和擦除这种修饰的蛋白质。阅读器结构域抑制剂的开发主要集中在单个结构域上。设计阅读器结构域抑制剂的主要困难之一是，除了溴结构域外，它们往往不具有封闭的适合小分子抑制的结合部位。由于许多参与表观遗传调控的蛋白质具有多个结构域，因此有机会设计出结合在结构域-结构域界面上的抑制剂，从而提供更合适的相互作用口袋。使用Sitemap算法对涉及识别和修改翻译后组蛋白标记的多个结构域的X射线结构进行检查，确定了结构域-结构域界面上的潜在结合位点。对于SP100C的串联植物同源结构域-溴结构域，通过X射线晶体片段筛选发现的配体，从实验上验证了计算确定的潜在的结构域间位点。
Epigenetics is a rapidly growing field in drug discovery. Of particular interest is the role of post‐translational modifications to histones and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains is that, with the notable exception of bromodomains, they tend not to possess a well‐enclosed binding site amenable to small‐molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains, there are opportunities for designing inhibitors that bind at a domain–domain interface which provide a more suitable interaction pocket. Examination of X‐ray structures of multiple domains involved in recognising and modifying post‐translational histone marks using the SiteMap algorithm identified potential binding sites at domain–domain interfaces. For the tandem plant homeodomain–bromodomain of SP100C, a potential inter‐domain site identified computationally was validated experimentally by the discovery of ligands by X‐ray crystallographic fragment screening.
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影响因子：
8.4
作者：
Hopkinson RJ;Tumber A;Yapp C;Chowdhury R;Aik W;Che KH;Li XS;Kristensen JBL;King ONF;Chan MC;Yeoh KK;Choi H;Walport LJ;Thinnes CC;Bush JT;Lejeune C;Rydzik AM;Rose NR;Bagg EA;McDonough MA;Krojer T;Yue WW;Ng SS;Olsen L;Brennan PE;Oppermann U;Muller-Knapp S;Klose RJ;Ratcliffe PJ;Schofield CJ;Kawamura A
通讯作者：
Kawamura A
DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
64.8
作者：
Lasko LM;Jakob CG;Edalji RP;Qiu W;Montgomery D;Digiammarino EL;Hansen TM;Risi RM;Frey R;Manaves V;Shaw B;Algire M;Hessler P;Lam LT;Uziel T;Faivre E;Ferguson D;Buchanan FG;Martin RL;Torrent M;Chiang GG;Karukurichi K;Langston JW;Weinert BT;Choudhary C;de Vries P;Van Drie JH;McElligott D;Kesicki E;Marmorstein R;Sun C;Cole PA;Rosenberg SH;Michaelides MR;Lai A;Bromberg KD
通讯作者：
Bromberg KD
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
5.6
作者：
Halgren, Thomas A.
通讯作者：
Halgren, Thomas A.