GPCR agonist binding revealed by modeling and crystallography.
GPCR agonist binding revealed by modeling and crystallography.
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DOI：
10.1016/j.tips.2011.08.001
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发表时间：
2011-11
影响因子：
13.8
通讯作者：
Abagyan R
中科院分区：
文献类型：
--
作者：
Katritch V;Abagyan R
虽然G-蛋白偶联受体（GPCR）家族的结构覆盖率稳步提高，这些膜蛋白的高可塑性提出了额外的挑战，其与不同类别的配体，特别是激动剂的复合物的晶体学研究。因此，从非活性GPCR结构开始，计算预测天然和临床相关激动剂的结合以及受体口袋中的相应变化的能力对于理解GPCR生物学和药物作用具有极大的意义。将2009年和2010年发表的计算模型与最近确定的β-肾上腺素能和腺苷A2 A受体的激动剂结合结构进行比较，发现预测的激动剂结合位姿（分别为0.8 μ m和1.7 μ m）和受体相互作用的准确性很高。在β2AR的情况下，具有有限主链柔性的基于能量的模型也允许将侧链旋转和口袋区域中的有限主链位移表征为完全、部分或反向激动作用的决定因素。其他GPCR激动剂结合的准确模型的开发将有助于功能和药理学研究，补充生物化学和晶体学技术。
While structural coverage of the G-protein coupled receptor (GPCR) family steadily improves, high plasticity of these membrane proteins poses additional challenges for crystallographic studies of their complexes with different classes of ligands, especially agonists. Ability to computationally predict binding of natural and clinically relevant agonists and corresponding changes in the receptor pocket, starting from inactive GPCR structures, is therefore of great interest for understanding GPCR biology and drug action. Comparison of published in 2009 and 2010 computational models with recently determined agonist-bound structures of β-adrenergic and adenosine A2A receptors reveals high accuracy of the predicted agonist binding poses (0.8 Å and 1.7 Å respectively) and receptor interactions. In the case of the β2AR, energy-based models with limited backbone flexibility also allowed characterization of side chain rotations and a finite backbone shift in the pocket region as determinants of full, partial or inverse agonism. Development of accurate models of agonist binding for other GPCRs will be instrumental for functional and pharmacological studies, complementing biochemical and crystallographic techniques.
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影响因子：
5.7
作者：
Kufareva, Irina;Rueda, Manuel;Katritch, Vsevolod;Stevens, Raymond C.;Abagyan, Ruben;Yoshikawa, Yasushi;Furuya, Toshio;Lee, Huisun;Roy, Ambrish;Grime, John;Rebehmed, Joseph;Zhang, Yang;Roumen, Luc;de Esch, Iwan J. P.;Leurs, Rob;de Graaf, Chris;Li, Youyong;Hou, Tingjun;Mysinger, Michael M.;Weiss, Dahlia R.;Irwin, John J.;Shoichet, Brian K.;McRobb, Fiona M.;Capuano, Ben;Crosby, Ian T.;Chalmers, David K.;Yuriev, Elizabeth;Wang, Qi;Mach, Robert H.;Reichert, David E.;Chuang, Gwo-Yu;Rognan, Didier;Simms, John;Sexton, Patrick;Wootten, Denise;Latek, Dorota;Ghoshdastider, Umesh;Filipek, Slawomir;Kirkpatrick, Andrea;Trzaskowski, Bartosz;Griffith, Adam;Kim, Soo-Kyung;Abrol, Ravinder;Goddard, William A., III;Vaidehi, Nagarajan;Lam, Alfonso;Bhattacharya, Supriyo;Li, Hubert;Balaraman, Gouthaman;Niesen, Michiel;Pal, Sandeep;Vorobjev, Yrii;Bakulina, Natalia;Solovyev, Victor;Beuming, Thijs;Costanzi, Stefano;Shi, Lei;Higgs, Chris;Salam, Noeris;Lupyan, Dmitry;Sherman, Woody;Ding, Feng;Kota, Pradeep;Ramachandran, Srinivas;Dokholyan, Nikolay V.;Carlsson, Jens;Coleman, Ryan G.;Fan, Hao;Schlessinger, Avner;Sali, Andrej;Tikhonova, Irina;Pogozheva, Irina;Lomize, Andrei;Hall, Nathan E.;Muddassar, Muhammad;Zhang, Yang;Pae, Ae Nim;Lee, Jooyoung;Lopez, Laura;Obiol-Pardo, Cristian;Selent, Jana;Mahboob, Sadia;Werner, Tim;Church, W. Bret;Brylinski, Michal;Ando, Tadashi;Guerler, Aysam;Zhou, Hongyi;Skolnick, Jeffrey;Xhaard, Henri;Jurkowski, Wiktor;Elofsson, Arne;Murad, Ahsan K.;Drwal, Malgorzata;Dupree, Tom B.;Griffith, Renate;Ostopovici-Halip, Liliana;Bologa, Cristian;Chen, K. M.;Sun, J.;Barth, Patrick;Yarov-Yarovoy, Vladimir;Baker, David;Vroling, Bas;Sanders, Marijn P. A.;Nabuurs, Sander B.;Nikiforovich, Gregory V.
通讯作者：
Nikiforovich, Gregory V.
DOI：
10.1073/pnas.0811065106
发表时间：
2009-03-24
影响因子：
11.1
作者：
Dror, Ron O.;Arlow, Daniel H.;Shaw, David E.
通讯作者：
Shaw, David E.
影响因子：
3.6
作者：
Hannawacker, A;Krasel, C;Lohse, MJ
通讯作者：
Lohse, MJ
影响因子：
4.7
作者：
Katritch, Vsevolod;Kufareva, Irina;Abagyan, Ruben
通讯作者：
Abagyan, Ruben
影响因子：
5.6
作者：
ABAGYAN, R;TOTROV, M
通讯作者：
TOTROV, M