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| | ==PAC1 GPCR Receptor complex== | | ==PAC1 GPCR Receptor complex== |
| - | <StructureSection load='6p9y' size='340' side='right'caption='[[6p9y]], [[Resolution|resolution]] 3.01Å' scene=''> | + | <SX load='6p9y' size='340' side='right' viewer='molstar' caption='[[6p9y]], [[Resolution|resolution]] 3.01Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6p9y]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P9Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P9Y FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6p9y]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P9Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P9Y FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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]] 3.01Å</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=6p9y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p9y OCA], [http://pdbe.org/6p9y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p9y RCSB], [http://www.ebi.ac.uk/pdbsum/6p9y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p9y ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=6p9y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p9y OCA], [https://pdbe.org/6p9y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p9y RCSB], [https://www.ebi.ac.uk/pdbsum/6p9y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p9y 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 (GPCRs) are important therapeutic targets for major diseases. Here, we present structures of peptide and Gs-bound pituitary adenylate cyclase-activating peptide, PAC1 receptor, and corticotropin-releasing factor (CRF), (CRF1) receptor. Together with recently solved structures, these provide coverage of the major class B GPCR subfamilies. Diverse orientations of the extracellular domain to the receptor core in different receptors are at least partially dependent on evolutionary conservation in the structure and nature of peptide interactions. Differences in peptide interactions to the receptor core also influence the interlinked TM2-TM1-TM6/ECL3/TM7 domain, and this is likely important in their diverse signaling. However, common conformational reorganization of ECL2, linked to reorganization of ICL2, modulates G protein contacts. Comparison between receptors reveals ICL2 as a key domain forming dynamic G protein interactions in a receptor- and ligand-specific manner. This work advances our understanding of class B GPCR activation and Gs coupling. |
| - | [[http://www.uniprot.org/uniprot/PACR_HUMAN PACR_HUMAN]] This is a receptor for PACAP-27 and PACAP-38. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. May regulate the release of adrenocorticotropin, luteinizing hormone, growth hormone, prolactin, epinephrine, and catecholamine. May play a role in spermatogenesis and sperm motility. Causes smooth muscle relaxation and secretion in the gastrointestinal tract. [[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/PACA_HUMAN PACA_HUMAN]] Binding to its receptor activates G proteins and stimulates adenylate cyclase in pituitary cells.<ref>PMID:11175907</ref>
| + | |
| | + | Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation.,Liang YL, Belousoff MJ, Zhao P, Koole C, Fletcher MM, Truong TT, Julita V, Christopoulos G, Xu HE, Zhang Y, Khoshouei M, Christopoulos A, Danev R, Sexton PM, Wootten D Mol Cell. 2020 Feb 6;77(3):656-668.e5. doi: 10.1016/j.molcel.2020.01.012. Epub, 2020 Jan 30. PMID:32004469<ref>PMID:32004469</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 6p9y" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Transducin 3D structures|Transducin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| - | </StructureSection> | + | </SX> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Lama glama]] |
| | [[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: Sexton, P]] | + | [[Category: Sexton P]] |
| - | [[Category: Gpcr]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| Structural highlights
Publication Abstract from PubMed
Class B G protein-coupled receptors (GPCRs) are important therapeutic targets for major diseases. Here, we present structures of peptide and Gs-bound pituitary adenylate cyclase-activating peptide, PAC1 receptor, and corticotropin-releasing factor (CRF), (CRF1) receptor. Together with recently solved structures, these provide coverage of the major class B GPCR subfamilies. Diverse orientations of the extracellular domain to the receptor core in different receptors are at least partially dependent on evolutionary conservation in the structure and nature of peptide interactions. Differences in peptide interactions to the receptor core also influence the interlinked TM2-TM1-TM6/ECL3/TM7 domain, and this is likely important in their diverse signaling. However, common conformational reorganization of ECL2, linked to reorganization of ICL2, modulates G protein contacts. Comparison between receptors reveals ICL2 as a key domain forming dynamic G protein interactions in a receptor- and ligand-specific manner. This work advances our understanding of class B GPCR activation and Gs coupling.
Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation.,Liang YL, Belousoff MJ, Zhao P, Koole C, Fletcher MM, Truong TT, Julita V, Christopoulos G, Xu HE, Zhang Y, Khoshouei M, Christopoulos A, Danev R, Sexton PM, Wootten D Mol Cell. 2020 Feb 6;77(3):656-668.e5. doi: 10.1016/j.molcel.2020.01.012. Epub, 2020 Jan 30. PMID:32004469[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Liang YL, Belousoff MJ, Zhao P, Koole C, Fletcher MM, Truong TT, Julita V, Christopoulos G, Xu HE, Zhang Y, Khoshouei M, Christopoulos A, Danev R, Sexton PM, Wootten D. Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation. Mol Cell. 2020 Feb 6;77(3):656-668.e5. doi: 10.1016/j.molcel.2020.01.012. Epub, 2020 Jan 30. PMID:32004469 doi:http://dx.doi.org/10.1016/j.molcel.2020.01.012
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