View source for 7s15


==GLP-1 receptor bound with Pfizer small molecule agonist==
<StructureSection load='7s15' size='340' side='right'caption='[[7s15]], [[Resolution|resolution]] 3.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7s15]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7S15 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S15 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=82L:2-[(4-{6-[(2,4-difluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic+acid'>82L</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=7s15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s15 OCA], [https://pdbe.org/7s15 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s15 RCSB], [https://www.ebi.ac.uk/pdbsum/7s15 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s15 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 of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor.,Griffith DA, Edmonds DJ, Fortin JP, Kalgutkar AS, Kuzmiski JB, Loria PM, Saxena AR, Bagley SW, Buckeridge C, Curto JM, Derksen DR, Dias JM, Griffor MC, Han S, Jackson VM, Landis MS, Lettiere D, Limberakis C, Liu Y, Mathiowetz AM, Patel JC, Piotrowski DW, Price DA, Ruggeri RB, Tess DA J Med Chem. 2022 Jun 1. doi: 10.1021/acs.jmedchem.1c01856. PMID:35647711<ref>PMID:35647711</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7s15" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Dias, J M]]
[[Category: Han, S]]
[[Category: Liu, Y]]
[[Category: Glp-1r]]
[[Category: Gpcr]]
[[Category: Membrane protein]]