Ligand-dependent activation and deactivation of the human adenosine A(2A) receptor.
Ligand-dependent activation and deactivation of the human adenosine A(2A) receptor.
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DOI：
10.1021/ja404391q
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发表时间：
2013-06-12
影响因子：
15
通讯作者：
Voth, Gregory A.
中科院分区：
文献类型：
--
作者：
Li, Jianing;Jonsson, Amanda L.;Beuming, Thijs;Shelley, John C.;Voth, Gregory A.
G蛋白偶联受体(GPCRs)是在细胞信号转导中起关键作用的膜蛋白，是一类主要的药物靶点。许多药物通过直接结合作用，调节GPCR活性，影响与多种疾病相关的信号通路。然而，配体依赖的GPCR激活/失活的完整细节很难从实验中获得。因此，目前还不清楚配体是如何调节GPCR的活性的。为了阐明A类GPCRs中人腺苷A2a受体(AA2AR)的配体依赖的激活/失活机制，我们对嵌入在膜中的该受体进行了大规模的无偏分子动力学和元动力学模拟。在原子水平上，我们观察到了类似于活跃态和非活跃态的不同结构状态。特别是，我们注意到关键的结构元素在构象转变过程中以高度一致的方式发生变化，包括色氨酸的六种构象状态(Trp2466.48)。我们的发现与之前提出的观点一致，即在激活过程中，色氨酸残基经历了一个旋转式转变，这可能与一系列连贯的构象变化相结合，导致G蛋白结合位点的打开。此外，元动力学模拟为这一机制提供了定量证据，表明配体结合如何改变活性和非活性状态之间的平衡。我们的分析还提出了一些特定的残基与兴奋/拮抗、亲和力和选择性有关，并认为配体结合口袋可以被认为有三个不同的区域，为基于结构的设计提供了动态特征。AA2AR与新配体结合的额外模拟与我们提出的机制一致。通常，除了在晶体结构中发现的情况外，我们的研究还提供了对配体依赖的AA2AR激活/失活的见解。这些结果应该有助于发现更有效和更有选择性的GPCR配体。
G protein-coupled receptors (GPCRs) are membrane proteins with critical functions in cellular signal transduction, representing a primary class of drug targets. Acting by direct binding, many drugs modulate GPCR activity and influence the signaling pathways associated with numerous diseases. However, complete details of ligand-dependent GPCR activation/deactivation are difficult to obtain from experiments. Therefore, it remains unclear how ligands modulate a GPCR’s activity. To elucidate the ligand-dependent activation/deactivation mechanism of the human adenosine A2A receptor (AA2AR), a member of the class A GPCRs, we performed large-scale unbiased molecular dynamics and metadynamics simulations of the receptor embedded in a membrane. At the atomic level, we have observed distinct structural states that resemble the active and inactive states. In particular we noted key structural elements changing in a highly concerted fashion during the conformational transitions, including six conformational states of a tryptophan (Trp2466.48). Our findings agree with a previously proposed view, that during activation, this tryptophan residue undergoes a rotameric transition that may be coupled to a series of coherent conformational changes, resulting in the opening of the G protein-binding site. Further, metadynamics simulations provide quantitative evidence for this mechanism, suggesting how ligand binding shifts the equilibrium between the active and inactive states. Our analysis also proposes that a few specific residues are associated with agonism/antagonism, affinity and selectivity, and suggests that the ligand-binding pocket can be thought of as having three distinct regions, providing dynamic features for structure-based design. Additional simulations with AA2AR bound to a novel ligand are consistent with our proposed mechanism. Generally, our study provides insights into the ligand-dependent AA2AR activation/deactivation in addition to what has been found in crystal structures. These results should aid in the discovery of more effective and selective GPCR ligands.
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影响因子：
2.9
作者：
Altenbach, C;Yang, K;Hubbell, WL
通讯作者：
Hubbell, WL
影响因子：
7.3
作者：
Hoffmann, C.;Zuern, A.;Lohse, M. J.
通讯作者：
Lohse, M. J.
影响因子：
3
作者：
Bonomi, M.;Barducci, A.;Parrinello, M.
通讯作者：
Parrinello, M.
DOI：
10.1073/pnas.1110499108
发表时间：
2011-11-15
影响因子：
11.1
作者：
Dror, Ron O.;Arlow, Daniel H.;Shaw, David E.
通讯作者：
Shaw, David E.
影响因子：
4.8
作者：
Ballesteros, JA;Jensen, AD;Javitch, JA
通讯作者：
Javitch, JA