|
|
| (3 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Non-peptide agonist (TT-OAD2) bound to the Glucagon-Like peptide-1 (GLP-1) Receptor== | | ==Non-peptide agonist (TT-OAD2) bound to the Glucagon-Like peptide-1 (GLP-1) Receptor== |
| - | <StructureSection load='6orv' size='340' side='right'caption='[[6orv]], [[Resolution|resolution]] 3.00Å' scene=''> | + | <SX load='6orv' size='340' side='right' viewer='molstar' caption='[[6orv]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6orv]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ORV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ORV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6orv]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ORV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ORV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N2V:N-{(3S,8S)-3-{4-[(3,4-dichlorophenyl)methoxy]phenyl}-7-[(1S)-1-phenylpropyl]-2,3,6,7,8,9-hexahydro[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-4-(2,3-dimethylpyridin-4-yl)-L-phenylalanine'>N2V</scene></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]] 3Å</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=6orv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6orv OCA], [http://pdbe.org/6orv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6orv RCSB], [http://www.ebi.ac.uk/pdbsum/6orv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6orv ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N2V:(2~{S})-2-[[(3~{S},8~{S})-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1~{S})-1-phenylpropyl]-3,6,8,9-tetrahydro-2~{H}-[1,4]dioxino[2,3-g]isoquinolin-8-yl]carbonylamino]-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoic+acid'>N2V</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=6orv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6orv OCA], [https://pdbe.org/6orv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6orv RCSB], [https://www.ebi.ac.uk/pdbsum/6orv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6orv ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | + | <div style="background-color:#fffaf0;"> |
| - | [[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.
| + | == Publication Abstract from PubMed == |
| - | == Function == | + | Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity(1). Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation(2-6). Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors. |
| - | [[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). [[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.
| + | |
| | + | Activation of the GLP-1 receptor by a non-peptidic agonist.,Zhao P, Liang YL, Belousoff MJ, Deganutti G, Fletcher MM, Willard FS, Bell MG, Christe ME, Sloop KW, Inoue A, Truong TT, Clydesdale L, Furness SGB, Christopoulos A, Wang MW, Miller LJ, Reynolds CA, Danev R, Sexton PM, Wootten D Nature. 2020 Jan;577(7790):432-436. doi: 10.1038/s41586-019-1902-z. Epub 2020 Jan, 8. PMID:31915381<ref>PMID:31915381</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 6orv" 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> | + | </SX> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Belousoff, M J]] | + | [[Category: Belousoff MJ]] |
| - | [[Category: Danev, R]] | + | [[Category: Danev R]] |
| - | [[Category: Liang, Y L]] | + | [[Category: Liang YL]] |
| - | [[Category: G-coupled protein receptor]]
| + | |
| - | [[Category: Gpcr]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Non-peptide angonist]]
| + | |
| Structural highlights
Publication Abstract from PubMed
Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity(1). Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation(2-6). Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors.
Activation of the GLP-1 receptor by a non-peptidic agonist.,Zhao P, Liang YL, Belousoff MJ, Deganutti G, Fletcher MM, Willard FS, Bell MG, Christe ME, Sloop KW, Inoue A, Truong TT, Clydesdale L, Furness SGB, Christopoulos A, Wang MW, Miller LJ, Reynolds CA, Danev R, Sexton PM, Wootten D Nature. 2020 Jan;577(7790):432-436. doi: 10.1038/s41586-019-1902-z. Epub 2020 Jan, 8. PMID:31915381[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zhao P, Liang YL, Belousoff MJ, Deganutti G, Fletcher MM, Willard FS, Bell MG, Christe ME, Sloop KW, Inoue A, Truong TT, Clydesdale L, Furness SGB, Christopoulos A, Wang MW, Miller LJ, Reynolds CA, Danev R, Sexton PM, Wootten D. Activation of the GLP-1 receptor by a non-peptidic agonist. Nature. 2020 Jan;577(7790):432-436. doi: 10.1038/s41586-019-1902-z. Epub 2020 Jan, 8. PMID:31915381 doi:http://dx.doi.org/10.1038/s41586-019-1902-z
|
