Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation.
Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation.
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DOI：
10.1038/nature10136
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发表时间：
2011-05-18
期刊：
影响因子：
64.8
通讯作者：
Tate, Christopher G.
中科院分区：
文献类型：
--
作者：
Lebon, Guillaume;Warne, Tony;Edwards, Patricia C.;Bennett, Kirstie;Langmead, Christopher J.;Leslie, Andrew G. W.;Tate, Christopher G.
腺苷受体和β-肾上腺素受体是G蛋白偶联受体（gpcr），它们分别在结合激动剂腺苷或去甲肾上腺素时激活细胞内G蛋白。gpcr具有类似的结构，由7个跨膜螺旋组成，包含保守性良好的序列基序，表明它们可能由共同的机制激活。最近的β-肾上腺素受体结构突出了跨膜区5中最初特异性结合激动剂而不是拮抗剂的残基，表明这些残基在激动剂诱导的受体激活中起重要作用，，。本文介绍了热稳定的人腺苷a2a受体（A2AR-GL31）与其内源性激动剂腺苷和合成激动剂NECA结合的两种晶体结构。这些结构代表了一种介于无活性和活性状态之间的中间构象，因为它们具有被认为处于完全激活状态的gpcr的所有特征，除了跨膜螺旋6的细胞质端部分阻塞了g蛋白结合位点。激动剂的腺嘌呤取代基以类似于逆激动剂ZM241385的化学相关区域的方式结合（参考文献）。这两种激动剂都含有一个在ZM241385中没有发现的rna基团，它深入到配体结合袋中，与H7中的保守残基（Ser 2777.42和His 2787.43；上标指Ballesteros-Weinstein编号）发生极性相互作用，并与H3中的残基发生非极性相互作用。相反，反向激动剂ZM241385不与这些残基相互作用，与激动剂结合结构的比较表明，ZM241385在空间上阻止了H5的构象变化，因此它是一种反向激动剂。A2AR的激动剂结合结构与β-肾上腺素受体的激动剂结合结构的比较表明，由螺旋3、5和7向内运动引起的配体结合袋的收缩可能是所有gpcr激活的共同特征。
Adenosine receptors and β-adrenoceptors are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins on binding the agonists adenosine or noradrenaline, respectively. GPCRs have similar structures consisting of seven transmembrane helices that contain well-conserved sequence motifs, indicating that they are probably activated by a common mechanism,. Recent structures of β-adrenoceptors highlight residues in transmembrane region 5 that initially bind specifically to agonists rather than to antagonists, indicating that these residues have an important role in agonist-induced activation of receptors,,. Here we present two crystal structures of the thermostabilized human adenosine A2Areceptor (A2AR-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. The structures represent an intermediate conformation between the inactive and active states, because they share all the features of GPCRs that are thought to be in a fully activated state, except that the cytoplasmic end of transmembrane helix 6 partially occludes the G-protein-binding site. The adenine substituent of the agonists binds in a similar fashion to the chemically related region of the inverse agonist ZM241385 (ref. ). Both agonists contain a ribose group, not found in ZM241385, which extends deep into the ligand-binding pocket where it makes polar interactions with conserved residues in H7 (Ser 2777.42and His 2787.43; superscripts refer to Ballesteros–Weinstein numbering) and non-polar interactions with residues in H3. In contrast, the inverse agonist ZM241385 does not interact with any of these residues and comparison with the agonist-bound structures indicates that ZM241385 sterically prevents the conformational change in H5 and therefore it acts as an inverse agonist. Comparison of the agonist-bound structures of A2AR with the agonist-bound structures of β-adrenoceptors indicates that the contraction of the ligand-binding pocket caused by the inward motion of helices 3, 5 and 7 may be a common feature in the activation of all GPCRs.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
DOI：
10.1073/pnas.0804396105
发表时间：
2008-08-05
影响因子：
11.1
作者：
Magnani, Francesca;Shibata, Yoko;Tate, Christopher G.
通讯作者：
Tate, Christopher G.
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
DOI：
10.1107/s0907444911008754
发表时间：
2011-05
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Gorrec F;Palmer CM;Lebon G;Warne T
通讯作者：
Warne T
影响因子：
5.6
作者：
Lebon G;Bennett K;Jazayeri A;Tate CG
通讯作者：
Tate CG