一种与激活微开关结构重排相关的腺苷受体部分激动作用。
A Adenosine Receptor Partial Agonism Related to Structural Rearrangements in an Activation Microswitch.
机构信息
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Departments of Biological Sciences and Chemistry, Bridge Institute, The University of Southern California, Los Angeles, CA 90089, USA; Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA.
Departments of Biological Sciences and Chemistry, Bridge Institute, The University of Southern California, Los Angeles, CA 90089, USA.
出版信息
Structure. 2021 Feb 4;29(2):170-176.e3. doi: 10.1016/j.str.2020.11.005. Epub 2020 Nov 24.
In drug design, G protein-coupled receptor (GPCR) partial agonists enable one to fine-tune receptor output between basal and maximal signaling levels. Here, we add to the structural basis for rationalizing and monitoring partial agonism. NMR spectroscopy of partial agonist complexes of the A adenosine receptor (AAR) revealed conformations of the P-I-F activation motif that are distinctly different from full agonist complexes. At the intracellular surface, different conformations of helix VI observed for partial and full agonist complexes manifest a correlation between the efficacy-related structural rearrangement of this activation motif and intracellular signaling to partner proteins. While comparisons of AAR in complexes with partial and full agonists with different methods showed close similarity of the global folds, this NMR study now reveals subtle but distinct local structural differences related to partial agonism.
在药物设计中，G 蛋白偶联受体 (GPCR) 部分激动剂可使受体输出在基础和最大信号水平之间进行微调。在这里，我们为合理化和监测部分激动作用增加了结构基础。通过对 A 腺苷受体 (AAR) 的部分激动剂复合物的 NMR 光谱研究，揭示了 P-I-F 激活基序的构象与完全激动剂复合物明显不同。在细胞内表面，对于部分和完全激动剂复合物观察到的不同构象的 VI 螺旋表明，该激活基序的与效能相关的结构重排与细胞内信号传递到伴侣蛋白之间存在相关性。虽然使用不同方法比较 AAR 与部分激动剂和完全激动剂复合物显示出整体折叠的高度相似性，但这项 NMR 研究现在揭示了与部分激动作用相关的微妙但明显的局部结构差异。
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