View source for 8jip


==Cryo-EM structure of the GLP-1R/GCGR dual agonist MEDI0382-bound human GLP-1R-Gs complex==
<StructureSection load='8jip' size='340' side='right'caption='[[8jip]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8jip]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8JIP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JIP FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D6M:N-HEXADECANOYL-L-GLUTAMIC+ACID'>D6M</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=8jip FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jip OCA], [https://pdbe.org/8jip PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jip RCSB], [https://www.ebi.ac.uk/pdbsum/8jip PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jip 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 ==
Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They share a high degree of sequence homology but have different functionalities. Unimolecular dual agonists of both receptors developed recently displayed better clinical efficacies than that of monotherapy. To study the underlying molecular mechanisms, we determined high-resolution cryo-electron microscopy structures of GLP-1R or GCGR in complex with heterotrimeric G(s) protein and three GLP-1R/GCGR dual agonists including peptide 15, MEDI0382 (cotadutide) and SAR425899 with variable activating profiles at GLP-1R versus GCGR. Compared with related structures reported previously and supported by our published pharmacological data, key residues responsible for ligand recognition and dual agonism were identified. Analyses of peptide conformational features revealed a difference in side chain orientations within the first three residues, indicating that distinct engagements in the deep binding pocket are required to achieve receptor selectivity. The middle region recognizes extracellular loop 1 (ECL1), ECL2, and the top of transmembrane helix 1 (TM1) resulting in specific conformational changes of both ligand and receptor, especially the dual agonists reshaped ECL1 conformation of GLP-1R relative to that of GCGR, suggesting an important role of ECL1 interaction in executing dual agonism. Structural investigation of lipid modification showed a better interaction between lipid moiety of MEDI0382 and TM1-TM2 cleft, in line with its increased potency at GCGR than SAR425899. Together, the results provide insightful information for the design and development of improved therapeutics targeting these two receptors simultaneously.

Structural analysis of the dual agonism at GLP-1R and GCGR.,Li Y, Zhou Q, Dai A, Zhao F, Chang R, Ying T, Wu B, Yang D, Wang MW, Cong Z Proc Natl Acad Sci U S A. 2023 Aug 15;120(33):e2303696120. doi: , 10.1073/pnas.2303696120. Epub 2023 Aug 7. PMID:37549266<ref>PMID:37549266</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8jip" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Escherichia coli]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Synthetic construct]]
[[Category: Chang RL]]
[[Category: Cong ZT]]
[[Category: Dai AT]]
[[Category: Wang MW]]
[[Category: Wu BL]]
[[Category: Yang DH]]
[[Category: Yang L]]
[[Category: Ying TL]]
[[Category: Zhao FH]]
[[Category: Zhou QT]]