5ott: Difference between revisions
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The | ==Extracellular domain of GLP-1 receptor in complex with exendin-4 variant Gly2Hcs/Thr5Hcs== | ||
<StructureSection load='5ott' size='340' side='right'caption='[[5ott]], [[Resolution|resolution]] 1.92Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5ott]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Heloderma_suspectum Heloderma suspectum] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OTT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OTT FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.92Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HCS:2-AMINO-4-MERCAPTO-BUTYRIC+ACID'>HCS</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ott FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ott OCA], [https://pdbe.org/5ott PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ott RCSB], [https://www.ebi.ac.uk/pdbsum/5ott PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ott ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GLP1R_HUMAN GLP1R_HUMAN] This is a receptor for glucagon-like peptide 1. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Peptide agonists acting on the glucagon-like peptide 1 receptor (GLP-1R) promote glucose-dependent insulin release and therefore represent important therapeutic agents for type 2 diabetes (T2D). Previous data indicated that an N-terminal type II beta-turn motif might be an important feature for agonists acting on the GLP-1R. In contrast, recent publications reporting the structure of the full-length GLP-1R have shown the N-terminus of receptor-bound agonists in an alpha-helical conformation. To reconcile these conflicting results, we prepared N-terminally constrained analogues of glucagon-like peptide 1 (GLP-1) and exendin-4 and evaluated their receptor affinity and functionality in vitro; we then examined their crystal structures in complex with the extracellular domain of the GLP-1R and used molecular modeling and molecular dynamics simulations for further investigations. We report that the peptides' N-termini in all determined crystal structures adopted a type II beta-turn conformation, but in vitro potency varied several thousand-fold across the series. Potency correlated better with alpha-helicity in our computational model, although we have found that the energy barrier between the two mentioned conformations is low in our most potent analogues and the flexibility of the N-terminus is highlighted by the dynamics simulations. | |||
alpha-Helix or beta-Turn? An Investigation into N-Terminally Constrained Analogues of Glucagon-like Peptide 1 (GLP-1) and Exendin-4.,Oddo A, Mortensen S, Thogersen H, De Maria L, Hennen S, McGuire JN, Kofoed J, Linderoth L, Reedtz-Runge S Biochemistry. 2018 Jun 21. doi: 10.1021/acs.biochem.8b00105. PMID:29877701<ref>PMID:29877701</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5ott" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Glucagon-like peptide receptor 3D structures|Glucagon-like peptide receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Heloderma suspectum]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Mortensen S]] | |||
Latest revision as of 12:16, 23 October 2024
Extracellular domain of GLP-1 receptor in complex with exendin-4 variant Gly2Hcs/Thr5HcsExtracellular domain of GLP-1 receptor in complex with exendin-4 variant Gly2Hcs/Thr5Hcs
Structural highlights
FunctionGLP1R_HUMAN This is a receptor for glucagon-like peptide 1. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. Publication Abstract from PubMedPeptide agonists acting on the glucagon-like peptide 1 receptor (GLP-1R) promote glucose-dependent insulin release and therefore represent important therapeutic agents for type 2 diabetes (T2D). Previous data indicated that an N-terminal type II beta-turn motif might be an important feature for agonists acting on the GLP-1R. In contrast, recent publications reporting the structure of the full-length GLP-1R have shown the N-terminus of receptor-bound agonists in an alpha-helical conformation. To reconcile these conflicting results, we prepared N-terminally constrained analogues of glucagon-like peptide 1 (GLP-1) and exendin-4 and evaluated their receptor affinity and functionality in vitro; we then examined their crystal structures in complex with the extracellular domain of the GLP-1R and used molecular modeling and molecular dynamics simulations for further investigations. We report that the peptides' N-termini in all determined crystal structures adopted a type II beta-turn conformation, but in vitro potency varied several thousand-fold across the series. Potency correlated better with alpha-helicity in our computational model, although we have found that the energy barrier between the two mentioned conformations is low in our most potent analogues and the flexibility of the N-terminus is highlighted by the dynamics simulations. alpha-Helix or beta-Turn? An Investigation into N-Terminally Constrained Analogues of Glucagon-like Peptide 1 (GLP-1) and Exendin-4.,Oddo A, Mortensen S, Thogersen H, De Maria L, Hennen S, McGuire JN, Kofoed J, Linderoth L, Reedtz-Runge S Biochemistry. 2018 Jun 21. doi: 10.1021/acs.biochem.8b00105. PMID:29877701[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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