期刊
NATURE CHEMICAL BIOLOGY
卷 18, 期 3, 页码 256-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-021-00945-w
关键词
-
资金
- National Institutes of Health [R01 GM056414]
- NSF [DGE1747503, DMB-8415048, OIA-9977486, BIR-9214394]
- Biotechnology Training Grant from NIGMS [T32 GM008349]
- Takeda Science Foundation
- Japan Science and Technology Agency PRESTO [18069571]
- ARC Centre Grant [IC200100052]
- National Health and Medical Research Council of Australia (NHMRC) Program Grant [1150083]
- Senior Principal Research Fellowship [1154434]
- NHMRC Project Grants [1126857, 1184726]
- NHMRC Senior Research Fellowship [1155302]
- NIH [P41GM136463, P41RR002301, P41GM103399, S10RR02781, S10RR08438, S10RR023438, S10RR025062, S10RR029220]
- University of Wisconsin-Madison
- National Health and Medical Research Council of Australia [1184726, 1126857, 1155302] Funding Source: NHMRC
- Australian Research Council [IC200100052] Funding Source: Australian Research Council
Recent advances in understanding the structures of G-protein-coupled receptors (GPCRs) have highlighted the importance of conformational flexibility in signal propagation. By studying the activation of the GLP-1 receptor, it was found that the conformational plasticity of peptide agonists plays a crucial role in determining agonist efficacy.
Recent advances in G-protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multidimensional signal propagation mediated by these receptors depends, in part, on their conformational mobility; however, the relationship between receptor function and static structures is inherently uncertain. Here, we examine the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide 1 receptor (GLP-1R), an important clinical target. We use variants of the peptides GLP-1 and exendin-4 (Ex4) to explore the interplay between helical propensity near the agonist N terminus and the ability to bind to and activate the receptor. Cryo-EM analysis of a complex involving an Ex4 analog, the GLP-1R and G(S) heterotrimer revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data, along with molecular dynamics (MD) simulations, suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据