For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
Inviting an author to review:
Equality on His Terms: Doing and Undoing Gender through Men’s Discussion Groups
Find an author and click ‘Invite to review selected article’ near their name.
Search for authorsSearch for similar articles
2
views
27
references
 Top references
cited by
92
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      146
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes.

          Abstract

          Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of inflammatory diseases. Here authors report a cryoelectron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, which provides insights into PACAP27 binding and VIP receptor activation.

          Related collections

          Most cited references27

          • Record: found
          • Abstract: found
          • Article: not found

          VPAC and PAC receptors: From ligands to function.

          Louise Dickson, Keith Finlayson (2009)
          Vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase activating polypeptides (PACAPs) share 68% identity at the amino acid level and belong to the secretin peptide family. Following the initial discovery of VIP almost four decades ago a substantial amount of knowledge has been presented describing the mechanisms of action, distribution and pleiotropic functions of these related peptides. It is now known that the physiological actions of these widely distributed peptides are produced through activation of three common G-protein coupled receptors (VPAC(1), VPAC(2) and PAC(1)R) which preferentially stimulate adenylate cyclase and increase intracellular cAMP, although stimulation of other intracellular messengers, including calcium and phospholipase D, has been reported. Using a range of in vitro and in vivo approaches, including cell-based functional assays, transgenic animals and rodent models of disease, VPAC/PAC receptor activation has been associated with numerous physiological processes (e.g. control of circadian rhythms) and clinical conditions (e.g. pulmonary hypertension), which underlies on-going research efforts and makes these peptides and their cognate receptors attractive targets for the pharmaceutical industry. However, despite the considerable interest in VPAC/PAC receptors and the processes which they mediate, there is still a paucity of selective and available, non-peptide ligands, which has hindered further advances in this field both at the basic research and clinical level. This review summarises the current knowledge of VIP/PACAP and the VPAC/PAC receptors with regard to their distribution, pharmacology, signalling pathways, splice variants and finally, the utility of animal models in exploring their physiological roles.
          Article 0 comments Cited 101 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations.

            Arthur Christopoulos, John Simms, Jeremy Hamilton-Miller … (2013)
            Recently, the concept of ligand-directed signaling--the ability of different ligands of an individual receptor to promote distinct patterns of cellular response--has gained much traction in the field of drug discovery, with the potential to sculpt biological response to favor therapeutically beneficial signaling pathways over those leading to harmful effects. However, there is limited understanding of the mechanistic basis underlying biased signaling. The glucagon-like peptide-1 receptor is a major target for treatment of type-2 diabetes and is subject to ligand-directed signaling. Here, we demonstrate the importance of polar transmembrane residues conserved within family B G protein-coupled receptors, not only for protein folding and expression, but also in controlling activation transition, ligand-biased, and pathway-biased signaling. Distinct clusters of polar residues were important for receptor activation and signal preference, globally changing the profile of receptor response to distinct peptide ligands, including endogenous ligands glucagon-like peptide-1, oxyntomodulin, and the clinically used mimetic exendin-4.
            Article 0 comments Cited 98 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Development of an antibody fragment that stabilizes GPCR/G-protein complexes

              Shoji Maeda, Antoine Koehl, Hugues Matile … (2018)
              Single-particle cryo-electron microscopy (cryo-EM) has recently enabled high-resolution structure determination of numerous biological macromolecular complexes. Despite this progress, the application of high-resolution cryo-EM to G protein coupled receptors (GPCRs) in complex with heterotrimeric G proteins remains challenging, owning to both the relative small size and the limited stability of these assemblies. Here we describe the development of antibody fragments that bind and stabilize GPCR-G protein complexes for the application of high-resolution cryo-EM. One antibody in particular, mAb16, stabilizes GPCR/G-protein complexes by recognizing an interface between Gα and Gβγ subunits in the heterotrimer, and confers resistance to GTPγS-triggered dissociation. The unique recognition mode of this antibody makes it possible to transfer its binding and stabilizing effect to other G-protein subtypes through minimal protein engineering. This antibody fragment is thus a broadly applicable tool for structural studies of GPCR/G-protein complexes.
              Article 0 comments Cited 93 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Yan Zhang:
                ORCID: http://orcid.org/0000-0003-2189-0244
                zhang_yan@zju.edu.cn
                H. Eric Xu:
                ORCID: http://orcid.org/0000-0002-6829-8144
                eric.xu@simm.ac.cn
                Yi Jiang:
                ORCID: http://orcid.org/0000-0002-0723-1413
                yijiang@simm.ac.cn
                Journal
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature Communications
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2041-1723
                Publication date (Electronic): 17 August 2020
                Publication date PMC-release: 17 August 2020
                Publication date Collection: 2020
                Volume: 11
                Electronic Location Identifier: 4121
                Affiliations
                [1 ]GRID grid.9227.e, ISNI 0000000119573309, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, , Chinese Academy of Sciences, ; Shanghai, 201203 China
                [2 ]GRID grid.410726.6, ISNI 0000 0004 1797 8419, University of Chinese Academy of Sciences, ; 100049 Beijing, China
                [3 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Pathology of Sir Run Run Shaw Hospital, , Zhejiang University School of Medicine, ; Hangzhou, 310058 China
                [4 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Biophysics, , Zhejiang University School of Medicine, ; Hangzhou, 310058 China
                [5 ]GRID grid.251017.0, ISNI 0000 0004 0406 2057, Center for Cancer and Cell Biology, Program for Structural Biology, , Van Andel Institute, ; Grand Rapids, MI USA
                [6 ]GRID grid.440637.2, ISNI 0000 0004 4657 8879, School of Life Science and Technology, , ShanghaiTech University, ; Shanghai, 201210 China
                Author information
                http://orcid.org/0000-0001-7813-5480
                http://orcid.org/0000-0002-9125-4027
                http://orcid.org/0000-0003-2189-0244
                http://orcid.org/0000-0002-6829-8144
                http://orcid.org/0000-0002-0723-1413
                Article
                Publisher ID: 17933
                DOI: 10.1038/s41467-020-17933-8
                PMC ID: 7431577
                PubMed ID: 32807782
                SO-VID: 7d9b10e4-96b7-459a-9546-96bc50fbd3b2
                Copyright © © The Author(s) 2020
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 30 January 2020
                Date accepted : 17 July 2020
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2020

                ScienceOpen disciplines: Uncategorized
                Keywords: g protein-coupled receptors,cryoelectron microscopy
                Data availability:
                ScienceOpen disciplines: Uncategorized
                Keywords: g protein-coupled receptors, cryoelectron microscopy

                Comments

                Comment on this article

                scite_

                Similar content146

                See all similar

                Cited by91

                See all cited by

                Most referenced authors1,118

                See all reference authors