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对与β2 - 肾上腺素能受体结合的完全激动剂和部分激动剂的分析表明,跨膜螺旋V在激动剂特异性构象变化中起作用。

Analysis of full and partial agonists binding to beta2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes.

作者信息

Katritch Vsevolod, Reynolds Kimberly A, Cherezov Vadim, Hanson Michael A, Roth Christopher B, Yeager Mark, Abagyan Ruben

机构信息

Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

出版信息

J Mol Recognit. 2009 Jul-Aug;22(4):307-18. doi: 10.1002/jmr.949.

Abstract

The 2.4 A crystal structure of the beta(2)-adrenergic receptor (beta(2)AR) in complex with the high-affinity inverse agonist (-)-carazolol provides a detailed structural framework for the analysis of ligand recognition by adrenergic receptors. Insights into agonist binding and the corresponding conformational changes triggering G-protein coupled receptor (GPCR) activation mechanism are of special interest. Here we show that while the carazolol pocket captured in the beta(2)AR crystal structure accommodates (-)-isoproterenol and other agonists without steric clashes, a finite movement of the flexible extracellular part of TM-V helix (TM-Ve) obtained by receptor optimization in the presence of docked ligand can further improve the calculated binding affinities for agonist compounds. Tilting of TM-Ve towards the receptor axis provides a more complete description of polar receptor-ligand interactions for full and partial agonists, by enabling optimal engagement of agonists with two experimentally identified anchor sites, formed by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Further, receptor models incorporating a flexible TM-V backbone allow reliable prediction of binding affinities for a set of diverse ligands, suggesting potential utility of this approach to design of effective and subtype-specific agonists for adrenergic receptors. Systematic differences in capacity of partial, full and inverse agonists to induce TM-V helix tilt in the beta(2)AR model suggest potential role of TM-V as a conformational "rheostat" involved in the whole spectrum of beta(2)AR responses to small molecule signals.

摘要

β₂ - 肾上腺素能受体(β₂AR)与高亲和力反向激动剂(-)-咔唑洛尔复合物的2.4 Å晶体结构为分析肾上腺素能受体的配体识别提供了详细的结构框架。深入了解激动剂结合以及触发G蛋白偶联受体(GPCR)激活机制的相应构象变化尤其令人感兴趣。在此我们表明,虽然β₂AR晶体结构中捕获的咔唑洛尔口袋可容纳(-)-异丙肾上腺素和其他激动剂而无空间冲突,但在对接配体存在下通过受体优化获得的TM - V螺旋(TM - Ve)柔性细胞外部分的有限移动可进一步提高计算出的激动剂化合物的结合亲和力。TM - Ve向受体轴倾斜,通过使激动剂与由Asp113/Asn312和Ser203/Ser204/Ser207侧链形成的两个实验确定的锚定位点实现最佳结合,从而更完整地描述了完全和部分激动剂的极性受体 - 配体相互作用。此外,包含柔性TM - V主链的受体模型能够可靠地预测一组不同配体的结合亲和力,表明这种方法在设计有效的肾上腺素能受体亚型特异性激动剂方面具有潜在效用。β₂AR模型中部分、完全和反向激动剂诱导TM - V螺旋倾斜能力的系统差异表明,TM - V作为构象“变阻器”在β₂AR对小分子信号的整个反应谱中具有潜在作用。

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