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Mass spectrometry captures biased signalling and allosteric modulation of a G-protein-coupled receptor.

التفاصيل البيبلوغرافية
العنوان: Mass spectrometry captures biased signalling and allosteric modulation of a G-protein-coupled receptor.
المؤلفون: Yen HY; Chemical Research Laboratory, University of Oxford, Oxford, UK. hsinyungyen@gate.sinica.edu.tw.; OMass Therapeutics, Oxford, UK. hsinyungyen@gate.sinica.edu.tw.; Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. hsinyungyen@gate.sinica.edu.tw., Liko I; Chemical Research Laboratory, University of Oxford, Oxford, UK.; OMass Therapeutics, Oxford, UK., Song W; Department of Biochemistry, University of Oxford, Oxford, UK.; Rahko, London, UK., Kapoor P; OMass Therapeutics, Oxford, UK., Almeida F; OMass Therapeutics, Oxford, UK., Toporowska J; Department of Chemistry, King's College London, London, UK., Gherbi K; OMass Therapeutics, Oxford, UK., Hopper JTS; OMass Therapeutics, Oxford, UK., Charlton SJ; OMass Therapeutics, Oxford, UK.; School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK., Politis A; Department of Chemistry, King's College London, London, UK.; Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, UK., Sansom MSP; Department of Biochemistry, University of Oxford, Oxford, UK., Jazayeri A; OMass Therapeutics, Oxford, UK. ali.jazayeri@omass.com., Robinson CV; Chemical Research Laboratory, University of Oxford, Oxford, UK. carol.robinson@chem.ox.ac.uk.; Kavli Institute for Nanoscience Discovery, Oxford, UK. carol.robinson@chem.ox.ac.uk.
المصدر: Nature chemistry [Nat Chem] 2022 Dec; Vol. 14 (12), pp. 1375-1382. Date of Electronic Publication: 2022 Nov 10.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101499734 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1755-4349 (Electronic) Linking ISSN: 17554330 NLM ISO Abbreviation: Nat Chem Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Pub. Group
مواضيع طبية MeSH: Receptors, Adrenergic, beta-2*/chemistry , Receptors, Adrenergic, beta-2*/metabolism , Receptors, G-Protein-Coupled*/metabolism, Allosteric Regulation ; Isoproterenol/pharmacology ; Ligands ; GTP-Binding Proteins/metabolism ; Ions ; Mass Spectrometry ; Zinc/metabolism
مستخلص: G-protein-coupled receptors signal through cognate G proteins. Despite the widespread importance of these receptors, their regulatory mechanisms for G-protein selectivity are not fully understood. Here we present a native mass spectrometry-based approach to interrogate both biased signalling and allosteric modulation of the β 1 -adrenergic receptor in response to various ligands. By simultaneously capturing the effects of ligand binding and receptor coupling to different G proteins, we probed the relative importance of specific interactions with the receptor through systematic changes in 14 ligands, including isoprenaline derivatives, full and partial agonists, and antagonists. We observed enhanced dynamics of the intracellular loop 3 in the presence of isoprenaline, which is capable of acting as a biased agonist. We also show here that endogenous zinc ions augment the binding in receptor-G s complexes and propose a zinc ion-binding hotspot at the TM5/TM6 intracellular interface of the receptor-G s complex. Further interrogation led us to propose a mechanism in which zinc ions facilitate a structural transition of the intermediate complex towards the stable state.
(© 2022. The Author(s).)
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معلومات مُعتمدة: 221795 United Kingdom WT_ Wellcome Trust; 092970/Z/10/Z United Kingdom WT_ Wellcome Trust; BB/L002558/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; 092970 United Kingdom WT_ Wellcome Trust; United Kingdom WT_ Wellcome Trust; 221795/Z/20/Z United Kingdom WT_ Wellcome Trust
سلسلة جزيئية: figshare 10.6084/m9.figshare.19688640; 10.6084/m9.figshare.19754662.v1
المشرفين على المادة: 0 (Receptors, Adrenergic, beta-2)
L628TT009W (Isoproterenol)
0 (Receptors, G-Protein-Coupled)
0 (Ligands)
EC 3.6.1.- (GTP-Binding Proteins)
0 (Ions)
J41CSQ7QDS (Zinc)
تواريخ الأحداث: Date Created: 20221111 Date Completed: 20221220 Latest Revision: 20240706
رمز التحديث: 20240706
مُعرف محوري في PubMed: PMC9758051
DOI: 10.1038/s41557-022-01041-9
PMID: 36357787
قاعدة البيانات: MEDLINE
الوصف
تدمد:1755-4349
DOI:10.1038/s41557-022-01041-9