Suppr超能文献

GPCRs 中高亲和力激动剂结合的分子基础。

Molecular basis for high-affinity agonist binding in GPCRs.

机构信息

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.

出版信息

Science. 2019 May 24;364(6442):775-778. doi: 10.1126/science.aau5595. Epub 2019 May 9.

Abstract

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.

摘要

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。

相似文献

1
Molecular basis for high-affinity agonist binding in GPCRs.
Science. 2019 May 24;364(6442):775-778. doi: 10.1126/science.aau5595. Epub 2019 May 9.
2
The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor.
Nature. 2011 Jan 13;469(7329):241-4. doi: 10.1038/nature09746.
3
Agonist-bound structures of G protein-coupled receptors.
Curr Opin Struct Biol. 2012 Aug;22(4):482-90. doi: 10.1016/j.sbi.2012.03.007. Epub 2012 Apr 3.
4
Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor.
Nature. 2016 Feb 11;530(7589):237-41. doi: 10.1038/nature16577. Epub 2016 Feb 3.
5
Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation.
Nature. 2016 Jul 21;535(7612):448-52. doi: 10.1038/nature18636. Epub 2016 Jul 13.
6
Structure-Based Prediction of G-Protein-Coupled Receptor Ligand Function: A β-Adrenoceptor Case Study.
J Chem Inf Model. 2015 May 26;55(5):1045-61. doi: 10.1021/acs.jcim.5b00066. Epub 2015 May 1.
7
Quantifying conformational changes in GPCRs: glimpse of a common functional mechanism.
BMC Bioinformatics. 2015 Apr 23;16(1):124. doi: 10.1186/s12859-015-0567-3.
8
High Pressure Shifts the β-Adrenergic Receptor to the Active Conformation in the Absence of G Protein.
J Am Chem Soc. 2019 Oct 23;141(42):16663-16670. doi: 10.1021/jacs.9b06042. Epub 2019 Oct 11.
9
Crystal structure of oligomeric β1-adrenergic G protein-coupled receptors in ligand-free basal state.
Nat Struct Mol Biol. 2013 Apr;20(4):419-25. doi: 10.1038/nsmb.2504. Epub 2013 Feb 24.
10
GPCRs through the keyhole: the role of protein flexibility in ligand binding to β-adrenoceptors.
J Biomol Struct Dyn. 2017 Sep;35(12):2604-2619. doi: 10.1080/07391102.2016.1226197. Epub 2016 Sep 1.

引用本文的文献

1
Enhanced Sampling and Tailored Collective Variables Yield Reproducible Free Energy Landscapes of Beta-1 Adrenergic Receptor Activation.
J Chem Theory Comput. 2025 Aug 12;21(15):7687-7700. doi: 10.1021/acs.jctc.5c00600. Epub 2025 Jul 28.
3
Validation and Optimization of PURE Ribosome Display for Screening Synthetic Nanobody Libraries.
Antibodies (Basel). 2025 May 2;14(2):39. doi: 10.3390/antib14020039.
4
Arrestin recognizes GPCRs independently of the receptor state.
Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2501487122. doi: 10.1073/pnas.2501487122. Epub 2025 May 15.
5
Structural insights into small-molecule agonist recognition and activation of complement receptor C3aR.
EMBO J. 2025 May;44(10):2803-2826. doi: 10.1038/s44318-025-00429-w. Epub 2025 Apr 7.
7
Intersection of GPCR trafficking and cAMP signaling at endomembranes.
J Cell Biol. 2025 Apr 7;224(4). doi: 10.1083/jcb.202409027. Epub 2025 Mar 25.
8
Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.
Nat Rev Drug Discov. 2025 Apr;24(4):251-275. doi: 10.1038/s41573-024-01083-3. Epub 2025 Jan 2.
9
10
Calcineurin-fusion facilitates cryo-EM structure determination of a Family A GPCR.
Proc Natl Acad Sci U S A. 2024 Nov 26;121(48):e2414544121. doi: 10.1073/pnas.2414544121. Epub 2024 Nov 20.

本文引用的文献

1
Single-molecule analysis of ligand efficacy in βAR-G-protein activation.
Nature. 2017 Jul 6;547(7661):68-73. doi: 10.1038/nature22354. Epub 2017 Jun 7.
2
Expression and Purification of Mini G Proteins from .
Bio Protoc. 2017 Apr 20;7(8). doi: 10.21769/BioProtoc.2235.
3
Engineering a minimal G protein to facilitate crystallisation of G protein-coupled receptors in their active conformation.
Protein Eng Des Sel. 2016 Dec;29(12):583-594. doi: 10.1093/protein/gzw049. Epub 2016 Sep 26.
4
Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region.
Nature. 2016 Aug 25;536(7617):484-7. doi: 10.1038/nature19107. Epub 2016 Aug 15.
5
Allosteric coupling from G protein to the agonist-binding pocket in GPCRs.
Nature. 2016 Jul 7;535(7610):182-6. doi: 10.1038/nature18324. Epub 2016 Jun 29.
6
Activation of the A2A adenosine G-protein-coupled receptor by conformational selection.
Nature. 2016 May 12;533(7602):265-8. doi: 10.1038/nature17668. Epub 2016 May 4.
7
Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling.
Cell. 2015 May 21;161(5):1101-1111. doi: 10.1016/j.cell.2015.04.043. Epub 2015 May 14.
8
POVME 2.0: An Enhanced Tool for Determining Pocket Shape and Volume Characteristics.
J Chem Theory Comput. 2014 Nov 11;10(11):5047-5056. doi: 10.1021/ct500381c. Epub 2014 Sep 29.
10
Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody.
Nature. 2013 Oct 24;502(7472):575-579. doi: 10.1038/nature12572. Epub 2013 Sep 22.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验