Application of an Integrated GPCR SAR-Modeling Platform To Explain the Activation Selectivity of Human 5-HT2C over 5-HT2B.
Application of an Integrated GPCR SAR-Modeling Platform To Explain the Activation Selectivity of Human 5-HT2C over 5-HT2B.
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应用集成 GPCR SAR 建模平台解释人 5-HT2C 相对于 5-HT2B 的激活选择性。
DOI：
10.1021/acschembio.5b01045
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发表时间：
2016
影响因子：
4
通讯作者：
Heifetz A
中科院分区：
文献类型：
--
作者：
Heifetz A
Agonism of the 5-HT2Cserotonin receptor has been associated with the treatment of a number of diseases including obesity, psychiatric disorders, sexual health, and urology. However, the development of effective 5-HT2Cagonists has been hampered by the difficulty in obtaining selectivity over the closely related 5-HT2Breceptor, agonism of which is associated with irreversible cardiac valvulopathy. Understanding how to design selective agonists requires exploration of the structural features governing the functional uniqueness of the target receptor relative to related off targets. X-ray crystallography, the major experimental source of structural information, is a slow and challenging process for integral membrane proteins, and so is currently not feasible for every GPCR or GPCR–ligand complex. Therefore, the integration of existing ligand SAR data with GPCR modeling can be a practical alternative to provide this essential structural insight. To demonstrate this, we integrated SAR data from 39 azepine series 5-HT2Cagonists, comprising both selective and unselective examples, with our hierarchical GPCR modeling protocol (HGMP). Through this work we have been able to demonstrate how relatively small differences in the amino acid sequences of GPCRs can lead to significant differences in secondary structure and function, as supported by experimental data. In particular, this study suggests that conformational differences in the tilt of TM7 between 5-HT2Band 5-HT2C, which result from differences in interhelical interactions, may be the major source of selectivity in G-protein activation between these two receptors. Our approach also demonstrates how the use of GPCR models in conjunction with SAR data can be used to explain activity cliffs.
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影响因子：
2.9
作者：
Heifetz, Alexander;Barker, Oliver;Morris, G. Benjamin;Law, Richard J.;Slack, Mark;Biggin, Philip C.
通讯作者：
Biggin, Philip C.
2-(3-氯苄氧基)-6-(哌嗪基)吡嗪（一种用于治疗肥胖的新型 5-羟色胺2c 受体激动剂）的基因毒性：代谢激活的作用
影响因子：
3.9
作者：
A. Kalgutkar;D. Dalvie;J. Aubrecht;Evan B. Smith;S. Coffing;J. Cheung;C. Vage;M. Lame;Phoebe Chiang;K. McClure;T. Maurer;Richard V. Coelho;V. Soliman;K. Schildknegt
通讯作者：
K. Schildknegt
影响因子：
4.7
作者：
J. Siuciak;D. Chapin;S. McCarthy;V. Guanowsky;Janice A. Brown;Phoebe Chiang;R. Marala;T. Patterson;P. Seymour;A. Swick;P. Iredale
通讯作者：
J. Siuciak;D. Chapin;S. McCarthy;V. Guanowsky;Janice A. Brown;Phoebe Chiang;R. Marala;T. Patterson;P. Seymour;A. Swick;P. Iredale
影响因子：
7.3
作者：
Heifetz, Alexander;Bodkin, Mike J.;Biggin, Philip C.
通讯作者：
Biggin, Philip C.
影响因子：
6.8
作者：
Steyaert J;Kobilka BK
通讯作者：
Kobilka BK