Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor.
Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor.
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作者：
G蛋白偶联受体（GPCR）是介导大多数细胞对激素和神经递质的反应的七种跨膜蛋白。它们是广泛疾病的最大治疗靶点组。最近的晶体结构的GPCR揭示了结构保守性延伸的正构配体结合位点的跨膜核心的细胞质G蛋白偶联结构域。相比之下，GPCR的细胞外表面（ECS）是非常多样的，因此代表了发现亚型选择性药物的理想靶点。然而，很少有人知道ECS在受体活化中的功能作用，或关于该表面与天然配体结合口袋的构象偶联。在这里，我们使用NMR光谱研究β2肾上腺素能受体ECS中中心结构特征周围的配体特异性构象变化：连接细胞外环（ECL）2和3的盐桥。结合在跨膜核心内并对G蛋白活化表现出不同功效的小分子药物（激动剂、中性拮抗剂和反向激动剂）也稳定ECS的不同构象。因此，我们证明了ECS和正构结合位点之间的构象耦合，表明靶向这种不同表面的药物可以作为具有高亚型选择性的变构调节剂发挥作用。此外，这些研究提供了新的见解GPCR的动态行为不能寻址静态，非活性状态的晶体结构。
G protein coupled receptors (GPCRs) are seven transmembrane proteins that mediate the majority of cellular responses to hormones and neurotransmitters. They are the largest group of therapeutic targets for a broad spectrum of diseases. Recent crystal structures of GPCRs reveal structural conservation extending from the orthosteric ligand binding site in the transmembrane core to the cytoplasmic G protein coupling domains. In contrast, the extracellular surface (ECS) of GPCRs is remarkably diverse, and therefore represents an ideal target for the discovery of subtype-selective drugs. However, little is known about the functional role of the ECS in receptor activation, or about conformational coupling of this surface to the native ligand binding pocket. Here we use NMR spectroscopy to investigate ligand-specific conformational changes around a central structural feature in the ECS of the β2 adrenergic receptor: a salt bridge linking extracellular loops (ECLs) 2 and 3. Small molecule drugs that bind within the transmembrane core and exhibit different efficacies towards G protein activation (agonist, neutral antagonist, and inverse agonist) also stabilize distinct conformations of the ECS. We thereby demonstrate conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity. Moreover, these studies provide new insight into the dynamic behavior of GPCRs not addressable by static, inactive-state crystal structures.
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DOI：
10.1038/nrd2760
发表时间：
2009-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
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影响因子：
4.8
作者：
Banères, JL;Mesnier, D;Bockaert, J
通讯作者：
Bockaert, J
影响因子：
4.8
作者：
Ghanouni, P;Gryczynski, Z;Kobilka, BK
通讯作者：
Kobilka, BK
影响因子：
64.8
作者：
Scheerer, Patrick;Park, Jung Hee;Ernst, Oliver P.
通讯作者：
Ernst, Oliver P.
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL