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==== | ==Cryo-EM structure of the INT-777-bound GPBAR-Gs complex== | ||
<StructureSection load='7cfn' size='340' side='right'caption='[[7cfn]]' scene=''> | <StructureSection load='7cfn' size='340' side='right'caption='[[7cfn]], [[Resolution|resolution]] 3.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7cfn]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] 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=7CFN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CFN FirstGlance]. <br> | ||
</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=7cfn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cfn OCA], [https://pdbe.org/7cfn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cfn RCSB], [https://www.ebi.ac.uk/pdbsum/7cfn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cfn ProSAT]</span></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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=FX0:(2~{S},4~{R})-4-[(3~{R},5~{S},6~{R},7~{R},8~{R},9~{S},10~{S},12~{S},13~{R},14~{S},17~{R})-6-ethyl-10,13-dimethyl-3,7,12-tris(oxidanyl)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a]phenanthren-17-yl]-2-methyl-pentanoic+acid'>FX0</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</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=7cfn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cfn OCA], [https://pdbe.org/7cfn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cfn RCSB], [https://www.ebi.ac.uk/pdbsum/7cfn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cfn ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://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 == | |||
[https://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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The G protein-coupled bile acid receptor (GPBAR) conveys the cross-membrane signaling of a vast variety of bile acids and is a signaling hub in the liver-bile-acid-microbiota-metabolism axis(1-3). Here, we report the cryo-EM structures of GPBAR-Gs complexes stabilized by either the high-affinity P395(4) or the semisynthesized bile acid derivative INT-777(1,3) at 3-A resolution. These structures revealed a large oval-shaped pocket containing several polar groups positioned to accommodate the amphipathic cholic core of bile acids, a fingerprint of key residues to recognize diverse bile acids in the orthosteric site, a putative second bile acid binding site with allosteric properties and structural features contributing to bias properties. Moreover, GPBAR undertakes an atypical mode of activation and G-protein coupling featuring a different set of key residues connecting the ligand binding pocket to the Gs coupling site, and a specific interaction motif localized in intracellular loop 3. Overall, our study not only reveals unique structural features of GPBAR involved in bile acid recognition and allosteric effects, but also suggests the presence of distinct connecting mechanisms between the ligand binding pocket and the G protein binding site in the GPCR superfamily. | |||
Structural basis of GPBAR activation and bile acid recognition.,Yang F, Mao C, Guo L, Lin J, Ming Q, Xiao P, Wu X, Shen Q, Guo S, Shen DD, Lu R, Zhang L, Huang S, Ping Y, Zhang C, Ma C, Zhang K, Liang X, Shen Y, Nan F, Yi F, Luca VC, Zhou J, Jiang C, Sun JP, Xie X, Yu X, Zhang Y Nature. 2020 Jul 22. pii: 10.1038/s41586-020-2569-1. doi:, 10.1038/s41586-020-2569-1. PMID:32698187<ref>PMID:32698187</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7cfn" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Transducin 3D structures|Transducin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Synthetic construct]] | ||
[[Category: Guo L]] | |||
[[Category: Guo S]] | |||
[[Category: Huang S]] | |||
[[Category: Jiang C]] | |||
[[Category: Liang X]] | |||
[[Category: Lin J]] | |||
[[Category: Lu R]] | |||
[[Category: Luca V]] | |||
[[Category: Ma C]] | |||
[[Category: Mao C]] | |||
[[Category: Ming Q]] | |||
[[Category: Nan F]] | |||
[[Category: Ping Y]] | |||
[[Category: Shen D]] | |||
[[Category: Shen Q]] | |||
[[Category: Shen Y]] | |||
[[Category: Sun J]] | |||
[[Category: Wu X]] | |||
[[Category: Xiao P]] | |||
[[Category: Xie X]] | |||
[[Category: Yang F]] | |||
[[Category: Yi F]] | |||
[[Category: Yu X]] | |||
[[Category: Zhang C]] | |||
[[Category: Zhang K]] | |||
[[Category: Zhang L]] | |||
[[Category: Zhang Y]] | |||
[[Category: Zhou J]] | |||
Latest revision as of 09:10, 21 November 2024
Cryo-EM structure of the INT-777-bound GPBAR-Gs complexCryo-EM structure of the INT-777-bound GPBAR-Gs complex
Structural highlights
DiseaseGNAS2_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. FunctionGNAS2_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).[1] [2] [3] [4] [5] Publication Abstract from PubMedThe G protein-coupled bile acid receptor (GPBAR) conveys the cross-membrane signaling of a vast variety of bile acids and is a signaling hub in the liver-bile-acid-microbiota-metabolism axis(1-3). Here, we report the cryo-EM structures of GPBAR-Gs complexes stabilized by either the high-affinity P395(4) or the semisynthesized bile acid derivative INT-777(1,3) at 3-A resolution. These structures revealed a large oval-shaped pocket containing several polar groups positioned to accommodate the amphipathic cholic core of bile acids, a fingerprint of key residues to recognize diverse bile acids in the orthosteric site, a putative second bile acid binding site with allosteric properties and structural features contributing to bias properties. Moreover, GPBAR undertakes an atypical mode of activation and G-protein coupling featuring a different set of key residues connecting the ligand binding pocket to the Gs coupling site, and a specific interaction motif localized in intracellular loop 3. Overall, our study not only reveals unique structural features of GPBAR involved in bile acid recognition and allosteric effects, but also suggests the presence of distinct connecting mechanisms between the ligand binding pocket and the G protein binding site in the GPCR superfamily. Structural basis of GPBAR activation and bile acid recognition.,Yang F, Mao C, Guo L, Lin J, Ming Q, Xiao P, Wu X, Shen Q, Guo S, Shen DD, Lu R, Zhang L, Huang S, Ping Y, Zhang C, Ma C, Zhang K, Liang X, Shen Y, Nan F, Yi F, Luca VC, Zhou J, Jiang C, Sun JP, Xie X, Yu X, Zhang Y Nature. 2020 Jul 22. pii: 10.1038/s41586-020-2569-1. doi:, 10.1038/s41586-020-2569-1. PMID:32698187[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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