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| | ==Extracellular domain of GLP-1 receptor in complex with exendin-4 variant Gly2Hcs/Thr5Hcs== | | ==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=''> | + | <StructureSection load='5ott' size='340' side='right'caption='[[5ott]], [[Resolution|resolution]] 1.92Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ott]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OTT FirstGlance]. <br> | + | <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='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=HCS:2-AMINO-4-MERCAPTO-BUTYRIC+ACID'>HCS</scene></td></tr> | + | </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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GLP1R ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ott FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ott OCA], [http://pdbe.org/5ott PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ott RCSB], [http://www.ebi.ac.uk/pdbsum/5ott PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ott ProSAT]</span></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> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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. [[http://www.uniprot.org/uniprot/EXE4_HELSU EXE4_HELSU]] Venom protein that mimics the incretin hormone glucagon-like peptide 1 (GLP-1). It stimulates insulin synthesis and secretion, protects against beta-cell apoptosis in response to different insults, and promotes beta-cell proliferation. It also promotes satiety, reduces food intake, reduces fat deposition, reduces body weight and inhibits gastric emptying. Interacts with GLP-1 receptor (GLP1R). Induces hypotension that is mediated by relaxation of cardiac smooth muscle.<ref>PMID:8405712</ref> <ref>PMID:19837656</ref> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5ott" style="background-color:#fffaf0;"></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 == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Heloderma suspectum]] |
| - | [[Category: Mortensen, S]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Cyclic peptide]] | + | [[Category: Large Structures]] |
| - | [[Category: Glucagon-like peptide 1]] | + | [[Category: Mortensen S]] |
| - | [[Category: Gpcr]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Function
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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Oddo A, Mortensen S, Thogersen H, De Maria L, Hennen S, McGuire JN, Kofoed J, Linderoth L, Reedtz-Runge S. alpha-Helix or beta-Turn? An Investigation into N-Terminally Constrained Analogues of Glucagon-like Peptide 1 (GLP-1) and Exendin-4. Biochemistry. 2018 Jun 21. doi: 10.1021/acs.biochem.8b00105. PMID:29877701 doi:http://dx.doi.org/10.1021/acs.biochem.8b00105
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