How Do Modulators Affect the Orthosteric and Allosteric Binding Pockets?
How Do Modulators Affect the Orthosteric and Allosteric Binding Pockets?
复制标题
DOI：
10.1021/acschemneuro.1c00749
复制
发表时间：
2022-04-06
影响因子：
5
通讯作者：
Feng, Zhiwei
中科院分区：
文献类型：
--
作者：
Chen, Chih-Jung;Jiang, Chen;Yuan, Jiayi;Chen, Maozi;Cuyler, Jacob;Xie, Xiang-Qun;Feng, Zhiwei
结合变构位点的变构调节剂（AMs）可以比正构配体表现出更大的选择性，并且可以增强激动剂诱导的受体活性（称为正变构调节剂或PAM），抑制激动剂诱导的活性（负变构调节剂或NAM），或者对活性没有影响（沉默AM或SAM）。到目前为止，尚不清楚AMs对正构活性位点或变构结合袋的确切影响。在目前的工作中，我们收集了特定靶蛋白的受体-正位配体和受体-正位配体- am复合物的三维结构。利用我们的新算法工具——分子复合物表征系统（MCCS），我们能够量化正构和变构结合位点的关键残基以及结合口袋的潜在变化。通过对21对三维晶体或冷冻电镜（cro - em）复合物（包括4对gpcr、5对离子通道、11对酶和1对转录因子）的分析，我们发现AMs的结合对正构和变构结合袋的影响都很小。反过来，我们可以准确地预测药物靶点的变构结合口袋，我们可以自信地进行虚拟筛选或先导优化，而不必担心口袋的巨大构象变化会导致虚拟筛选的准确性低。
Allosteric modulators (AMs) that bind allosteric sites can exhibit greater selectivity than the orthosteric ligands and can either enhance agonist-induced receptor activity (termed positive allosteric modulator or PAM), inhibit agonist-induced activity (negative AM or NAM), or have no effect on activity (silent AM or SAM). Until now, it is not clear what the exact effects of AMs are on the orthosteric active site or the allosteric binding pocket(s). In the present work, we collected both the three-dimensional (3D) structures of receptor–orthosteric ligand and receptor–orthosteric ligand–AM complexes of a specific target protein. Using our novel algorithm toolset, molecular complex characterizing system (MCCS), we were able to quantify the key residues in both the orthosteric and allosteric binding sites along with potential changes of the binding pockets. After analyzing 21 pairs of 3D crystal or cryo-electron microscopy (cryo-EM) complexes, including 4 pairs of GPCRs, 5 pairs of ion channels, 11 pairs of enzymes, and 1 pair of transcription factors, we found that the binding of AMs had little impact on both the orthosteric and allosteric binding pockets. In return, given the accurately predicted allosteric binding pocket(s) of a drug target of medicinal interest, we can confidently conduct the virtual screening or lead optimization without concern that the huge conformational change of the pocket could lead to the low accuracy of virtual screening.
登录
查看更多内容
影响因子：
64.8
作者：
Cho, HS;Mason, K;Leahy, DJ
通讯作者：
Leahy, DJ
影响因子：
2.9
作者：
Fischmann, Thierry O.;Smith, Catherine K.;Madison, Vincent S.
通讯作者：
Madison, Vincent S.
DOI：
10.3390/molecules22101551
发表时间：
2017-09-26
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Cheng Y;Tian H
通讯作者：
Tian H
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
影响因子：
2.7
作者：
Dong, Qing;Dougan, Douglas R.;Zhou, Feng
通讯作者：
Zhou, Feng