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-Structure paper
タイトル | Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 92, Year 2022 |
掲載日 | 2022年1月10日 |
![]() | Giuseppe Deganutti / Yi-Lynn Liang / Xin Zhang / Maryam Khoshouei / Lachlan Clydesdale / Matthew J Belousoff / Hari Venugopal / Tin T Truong / Alisa Glukhova / Andrew N Keller / Karen J Gregory / Katie Leach / Arthur Christopoulos / Radostin Danev / Christopher A Reynolds / Peishen Zhao / Patrick M Sexton / Denise Wootten / ![]() ![]() ![]() ![]() ![]() ![]() |
PubMed 要旨 | The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, ...The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists. |
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手法 | EM (単粒子) |
解像度 | 3.3 - 3.7 Å |
構造データ | EMDB-23425, PDB-7lll: EMDB-23436, PDB-7lly: |
由来 |
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![]() | MEMBRANE PROTEIN / Glucagon-Like Peptide-1 (GLP-1) Receptor / extendin-4 / Oxyntomodulin |