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摘要 : A2A腺苷受体(A2AR,一个A-类G-蛋白耦合受体)是多种疾病的一个重要药物作用目标。

 A2A腺苷受体(A2AR,一个A-类G-蛋白耦合受体)是多种疾病的一个重要药物作用目标。Scott Prosser及同事采用19F NMR来研究A2AR的动态,发现该受体以由处于平衡态的四个状态组成的一个整体形式存在:两个不活跃状态和两个活跃状态。添加一种逆向活化剂,会增加不活跃状态的数量。全活化剂(full agonist)能稳定其中一个活跃状态,而一种部分活化剂(partial agonist)或一种变构调节剂(allosteric modulator)的添加则只增加另一个活跃状态的数量。这表明,部分和全部活化都可以通过一个截然不同的活跃状态的构形选择实现。


Activation of the A2A adenosine G-protein-coupled receptor by conformational selection



Conformational selection and induced fit are two prevailing mechanisms1, 2 to explain the molecular basis for ligand-based activation of receptors. G-protein-coupled receptors are the largest class of cell surface receptors and are important drug targets. A molecular understanding of their activation mechanism is critical for drug discovery and design. However, direct evidence that addresses how agonist binding leads to the formation of an active receptor state is scarce3. Here we use 19F nuclear magnetic resonance to quantify the conformational landscape occupied by the adenosine A2A receptor (A2AR), a prototypical class A G-protein-coupled receptor. We find an ensemble of four states in equilibrium: (1) two inactive states in millisecond exchange, consistent with a formed (state S1) and a broken (state S2) salt bridge (known as ‘ionic lock’) between transmembrane helices 3 and 6; and (2) two active states, S3 and S3′, as identified by binding of a G-protein-derived peptide. In contrast to a recent study of the β2-adrenergic receptor4, the present approach allowed identification of a second active state for A2AR. Addition of inverse agonist (ZM241385) increases the population of the inactive states, while full agonists (UK432097 or NECA) stabilize the active state, S3′, in a manner consistent with conformational selection. In contrast, partial agonist (LUF5834) and an allosteric modulator (HMA) exclusively increase the population of the S3 state. Thus, partial agonism is achieved here by conformational selection of a distinct active state which we predict will have compromised coupling to the G protein. Direct observation of the conformational equilibria of ligand-dependent G-protein-coupled receptor and deduction of the underlying mechanisms of receptor activation will have wide-reaching implications for our understanding of the function of G-protein-coupled receptor in health and disease.

来源: Nature 浏览次数:0


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