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==3.3 angstrom phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex==
==3.3 angstrom phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex==
<StructureSection load='6b3j' size='340' side='right' caption='[[6b3j]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
<SX load='6b3j' size='340' side='right' viewer='molstar' caption='[[6b3j]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6b3j]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Camelus_glama Camelus glama] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B3J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B3J FirstGlance]. <br>
<table><tr><td colspan='2'>[[6b3j]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Lama_glama Lama glama] 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=6B3J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B3J FirstGlance]. <br>
</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]), GNAS, GNAS1, GSP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GNB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GNG2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.3&#8491;</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=6b3j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b3j OCA], [http://pdbe.org/6b3j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b3j RCSB], [http://www.ebi.ac.uk/pdbsum/6b3j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b3j 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=6b3j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b3j OCA], [https://pdbe.org/6b3j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b3j RCSB], [https://www.ebi.ac.uk/pdbsum/6b3j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b3j ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/GNAS2_HUMAN GNAS2_HUMAN]] Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_HUMAN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.<ref>PMID:18611381</ref>  [[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/GNAS2_HUMAN GNAS2_HUMAN]] Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).<ref>PMID:12391161</ref> <ref>PMID:17110384</ref> <ref>PMID:21488135</ref> <ref>PMID:26206488</ref> <ref>PMID:8702665</ref> [[http://www.uniprot.org/uniprot/GBG2_HUMAN GBG2_HUMAN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity).
[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 ==
The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity. Endogenous and mimetic GLP-1 peptides exhibit biased agonism-a difference in functional selectivity-that may provide improved therapeutic outcomes. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Galphas heterotrimer, determined at a global resolution of 3.3 A. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure. At the intracellular face, there was a six-degree difference in the angle of the Galphas-alpha5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the Galphas protein. Our structure provides insights into the molecular basis of biased agonism.
 
Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex.,Liang YL, Khoshouei M, Glukhova A, Furness SGB, Zhao P, Clydesdale L, Koole C, Truong TT, Thal DM, Lei S, Radjainia M, Danev R, Baumeister W, Wang MW, Miller LJ, Christopoulos A, Sexton PM, Wootten D Nature. 2018 Mar 1;555(7694):121-125. doi: 10.1038/nature25773. Epub 2018 Feb 21. PMID:29466332<ref>PMID:29466332</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6b3j" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Annexin 3D structures|Annexin 3D structures]]
*[[GTP-binding protein 3D structures|GTP-binding protein 3D structures]]
*[[Glucagon-like peptide receptor 3D structures|Glucagon-like peptide receptor 3D structures]]
*[[Transducin 3D structures|Transducin 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</SX>
[[Category: Camelus glama]]
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Lama glama]]
[[Category: Baumeister, W]]
[[Category: Large Structures]]
[[Category: Christopoulos, A]]
[[Category: Synthetic construct]]
[[Category: Clydesdale, L]]
[[Category: Baumeister W]]
[[Category: Danev, R]]
[[Category: Christopoulos A]]
[[Category: Furness, S G.B]]
[[Category: Clydesdale L]]
[[Category: Glukhova, A]]
[[Category: Danev R]]
[[Category: Khoshouei, M]]
[[Category: Furness SGB]]
[[Category: Koole, C]]
[[Category: Glukhova A]]
[[Category: Liang, Y L]]
[[Category: Khoshouei M]]
[[Category: Miller, L J]]
[[Category: Koole C]]
[[Category: Radjainia, M]]
[[Category: Liang YL]]
[[Category: Sexton, P M]]
[[Category: Miller LJ]]
[[Category: Thal, D M]]
[[Category: Radjainia M]]
[[Category: Wang, M W]]
[[Category: Sexton PM]]
[[Category: Wootten, D]]
[[Category: Thal DM]]
[[Category: Zhao, P]]
[[Category: Wang MW]]
[[Category: Active-state g protein-coupled receptor]]
[[Category: Wootten D]]
[[Category: Agonist-receptor-g protein ternary complex]]
[[Category: Zhao P]]
[[Category: Class b g protein-coupled receptor]]
[[Category: Glucagon-like peptide 1 receptor]]
[[Category: Phase contrast]]
[[Category: Phase plate]]
[[Category: Signaling protein]]
[[Category: Single particle cryo-em]]

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