Evidence map›Paper›PMID 26700562›Full record

ArticleMolecular pharmacology2016

A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures.

Denise Wootten, Christopher A Reynolds, Cassandra Koole, Kevin J Smith, Juan C Mobarec, John Simms, Tezz Quon, Thomas Coudrat, Sebastian G B Furness, Laurence J Miller and 2 more

Open access · bronzeAbstract read
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In one paragraph

Article in Molecular pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.

0numbers the graph read from it
0cells of the map it votes in
34citing papers in PubMed
3.6field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

34 citing papers in PubMed, 69 citations in OpenAlex.

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  11. Review
  12. Capturing Peptide-GPCR Interactions and Their Dynamics.Molecules (Basel, Switzerland) · 2020
    Review
  13. Article
  14. A combined activation mechanism for the glucagon receptor.Proceedings of the National Academy of Sciences of the United States of America · 2020
    Article
  15. Review
  16. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 4 institutions in 3 countries.

Denise WoottenMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.) denise.wootten@monash.edu patrick.sexton@monash.edu.
Christopher A ReynoldsMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
Cassandra KooleMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
Kevin J SmithMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
Juan C MobarecMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
John SimmsMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
Tezz QuonMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
Thomas CoudratMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
Sebastian G B FurnessMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
Laurence J MillerMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
Arthur ChristopoulosMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
Patrick M SextonMonash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., C.K., T.Q., T.C., S.G.B.F., A.C., P.M.S.); School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK (C.A.R., K.J.S., J.C.M.); School of Life and Health Sciences, Aston University, Birmingham, UK (J.S.); and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ (L.J.M.).
Aston University · GBMayo Clinic in Arizona · USMonash University · AUUniversity of Essex · GB

Funding

Biotechnology and Biological Sciences Research Council BB/M006883/1Medical Research Council G1001812
6 · The paper itself

Abstract

The glucagon-like peptide 1 (GLP-1) receptor is a class B G protein-coupled receptor (GPCR) that is a key target for treatments for type II diabetes and obesity. This receptor, like other class B GPCRs, displays biased agonism, though the physiologic significance of this is yet to be elucidated. Previous work has implicated R2.60(190), N3.43(240), Q7.49(394), and H6.52(363) as key residues involved in peptide-mediated biased agonism, with R2.60(190), N3.43(240), and Q7.49(394) predicted to form a polar interaction network. In this study, we used novel insight gained from recent crystal structures of the transmembrane domains of the glucagon and corticotropin releasing factor 1 (CRF1) receptors to develop improved models of the GLP-1 receptor that predict additional key molecular interactions with these amino acids. We have introduced E6.53(364)A, N3.43(240)Q, Q7.49(394)N, and N3.43(240)Q/Q7.49(394)N mutations to probe the role of predicted H-bonding and charge-charge interactions in driving cAMP, calcium, or extracellular signal-regulated kinase (ERK) signaling. A polar interaction between E6.53(364) and R2.60(190) was predicted to be important for GLP-1- and exendin-4-, but not oxyntomodulin-mediated cAMP formation and also ERK1/2 phosphorylation. In contrast, Q7.49(394), but not R2.60(190)/E6.53(364) was critical for calcium mobilization for all three peptides. Mutation of N3.43(240) and Q7.49(394) had differential effects on individual peptides, providing evidence for molecular differences in activation transition. Collectively, this work expands our understanding of peptide-mediated signaling from the GLP-1 receptor and the key role that the central polar network plays in these events.

Indexed as

Models, MolecularAnimalsCHO CellsCricetinaeCricetulusCrystallizationGlucagon-Like Peptide 1HumansHydrogen BondingPeptide FragmentsProtein BindingProtein Structure, SecondaryGlucagon-Like Peptide 1Peptide Fragments

Identifiers

PMID26700562
PMCPMC4767408
OpenAlexW2252989708

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.