Activation dynamics traced through a G protein-coupled receptor by 81 1H-15N NMR probes

• 成果类型: Article
• 署名作者: Wu, Feng-Jie; Rieder, Pascal S.; Abiko, Layara Akemi; Grahl, Anne; Haeussinger, Daniel; Grzesiek, Stephan
• 署名单位: University of Basel; University of Basel
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11948
• DOI: 10.1126/science.adq9106
• 发表日期: 2025-05-15
• 关键词: crystal-structure; structural insights; ligand efficacy; active state; agonist; crystallization; mechanisms; diversity; rhodopsin

摘要

The regulation of G protein-coupled receptor signaling by different orthosteric ligands is thought to occur through shifts in dynamically interconverting, conformational distributions. Such changes in dynamical distributions have been detected so far only by very sparse, often non-native experimental probes at low resolution. Using a recently developed paramagnetic nuclear magnetic resonance (NMR) method, we could assign and follow 81 H-1-N-15 NMR correlations in the beta(1)-adrenergic receptor beta(1)AR at ambient conditions in response to various orthosteric ligands in the absence or presence of a G protein-mimicking nanobody. The comparison reveals the dynamics and mechanism of the central, highly conserved xWIPF(3) motif, contiguous regions of rigid and loose conformational coupling separated by conserved prolines during signal transmission, and the plasticity of the intracellular face in response to transducer binding.