Medical Research Council (MRC) Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge CB21 6GT, UK.
Science. 2019 May 24;364(6442):775-778. doi: 10.1126/science.aau5595. Epub 2019 May 9.
G protein-coupled receptors (GPCRs) in the G protein-coupled active state have higher affinity for agonists as compared with when they are in the inactive state, but the molecular basis for this is unclear. We have determined four active-state structures of the β-adrenoceptor (βAR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of βAR bound to the identical ligands showed a 24 to 42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists.
G 蛋白偶联受体(GPCRs)在 G 蛋白偶联的激活状态下对激动剂的亲和力高于其在非激活状态下的亲和力,但这种现象的分子基础尚不清楚。我们已经确定了四种β-肾上腺素受体(βAR)与变构特异性纳米体结合的激活态结构,这些结构存在不同功效的激动剂。与βAR 与相同配体结合的非激活态结构进行比较,发现正位结合位点的体积减少了 24%至 42%。潜在氢键也更短,受体和配体之间的原子接触数量增加了高达 30%。这解释了 GPCR 在激活状态下对广泛的结构不同的激动剂的亲和力增加的原因。