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| | <SX load='6niy' size='340' side='right' viewer='molstar' caption='[[6niy]], [[Resolution|resolution]] 3.34Å' scene=''> | | <SX load='6niy' size='340' side='right' viewer='molstar' caption='[[6niy]], [[Resolution|resolution]] 3.34Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6niy]] 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=6NIY OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6NIY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6niy]] 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/Oncorhynchus_sp. Oncorhynchus sp.]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NIY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NIY FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5uz7|5uz7]]</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]] 3.34Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GNAS, GNAS1, GSP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CALCR ([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>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6niy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6niy OCA], [https://pdbe.org/6niy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6niy RCSB], [https://www.ebi.ac.uk/pdbsum/6niy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6niy ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6niy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6niy OCA], [http://pdbe.org/6niy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6niy RCSB], [http://www.ebi.ac.uk/pdbsum/6niy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6niy 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/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/CALCR_HUMAN CALCR_HUMAN]] This is a receptor for calcitonin. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. The calcitonin receptor is thought to couple to the heterotrimeric guanosine triphosphate-binding protein that is sensitive to cholera toxin. [[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/CALCR_HUMAN CALCR_HUMAN] This is a receptor for calcitonin. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. The calcitonin receptor is thought to couple to the heterotrimeric guanosine triphosphate-binding protein that is sensitive to cholera toxin. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </SX> | | </SX> |
| - | [[Category: Camelus glama]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Lama glama]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Atanasio, S]] | + | [[Category: Oncorhynchus sp]] |
| - | [[Category: Carazo, J M]] | + | [[Category: Atanasio S]] |
| - | [[Category: Christopoulos, A]] | + | [[Category: Carazo J-M]] |
| - | [[Category: Furness, S G.B]] | + | [[Category: Christopoulos A]] |
| - | [[Category: Garcia-Nafria, J]] | + | [[Category: Furness SGB]] |
| - | [[Category: Glukhova, A]] | + | [[Category: Garcia-Nafria J]] |
| - | [[Category: Hay, D L]] | + | [[Category: Glukhova A]] |
| - | [[Category: Hick, C A]] | + | [[Category: Hay DL]] |
| - | [[Category: Liang, Y L]] | + | [[Category: Hick CA]] |
| - | [[Category: Maso, E dal]]
| + | [[Category: Liang Y-L]] |
| - | [[Category: Miller, L J]] | + | [[Category: Miller LJ]] |
| - | [[Category: Ramirez-Aportela, E]] | + | [[Category: Ramirez-Aportela E]] |
| - | [[Category: Reynolds, C A]] | + | [[Category: Reynolds CA]] |
| - | [[Category: Sexton, P M]] | + | [[Category: Sexton PM]] |
| - | [[Category: Tate, C G]] | + | [[Category: Tate CG]] |
| - | [[Category: Wang, M W]] | + | [[Category: Wang M-W]] |
| - | [[Category: Wootten, D]] | + | [[Category: Wootten D]] |
| - | [[Category: Zhu, Y]] | + | [[Category: Zhu Y]] |
| - | [[Category: Calcitonin]] | + | [[Category: Dal Maso E]] |
| - | [[Category: Gpcr]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Receptor]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| Structural highlights
Function
CALCR_HUMAN This is a receptor for calcitonin. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. The calcitonin receptor is thought to couple to the heterotrimeric guanosine triphosphate-binding protein that is sensitive to cholera toxin.
Publication Abstract from PubMed
The calcitonin receptor (CTR) is a class B G protein-coupled receptor (GPCR) that responds to the peptide hormone calcitonin (CT). CTs are clinically approved for the treatment of bone diseases. We previously reported a 4.1 A structure of the activated CTR bound to salmon CT (sCT) and heterotrimeric Gs protein by cryo-electron microscopy (Liang, Y.-L., et al. Phase-plate cryo- EM structure of a class B GPCR-G protein complex. Nature 2017, 546, 118-123). In the current study, we have reprocessed the electron micrographs to yield a 3.3 A map of the complex. This has allowed us to model extracellular loops (ECLs) 2 and 3, and the peptide N-terminus that previously could not be resolved. We have also performed alanine scanning mutagenesis of ECL1 and the upper segment of transmembrane helix 1 (TM1) and its extension into the receptor extracellular domain (TM1 stalk), with effects on peptide binding and function assessed by cAMP accumulation and ERK1/2 phosphorylation. These data were combined with previously published alanine scanning mutagenesis of ECL2 and ECL3 and the new structural information to provide a comprehensive 3D map of the molecular surface of the CTR that controls binding and signaling of distinct CT and related peptides. The work highlights distinctions in how different, related, class B receptors may be activated. The new mutational data on the TM1 stalk and ECL1 have also provided critical insights into the divergent control of cAMP versus pERK signaling and, collectively with previous mutagenesis data, offer evidence that the conformations linked to these different signaling pathways are, in many ways, mutually exclusive. This study furthers our understanding of the complex nature of signaling elicited by GPCRs and, in particular, that of the therapeutically important class B subfamily.
The Molecular Control of Calcitonin Receptor Signaling.,Dal Maso E, Glukhova A, Zhu Y, Garcia-Nafria J, Tate CG, Atanasio S, Reynolds CA, Ramirez-Aportela E, Carazo JM, Hick CA, Furness SGB, Hay DL, Liang YL, Miller LJ, Christopoulos A, Wang MW, Wootten D, Sexton PM ACS Pharmacol Transl Sci. 2019 Jan 11;2(1):31-51. doi: 10.1021/acsptsci.8b00056. , eCollection 2019 Feb 8. PMID:32219215[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dal Maso E, Glukhova A, Zhu Y, Garcia-Nafria J, Tate CG, Atanasio S, Reynolds CA, Ramirez-Aportela E, Carazo JM, Hick CA, Furness SGB, Hay DL, Liang YL, Miller LJ, Christopoulos A, Wang MW, Wootten D, Sexton PM. The Molecular Control of Calcitonin Receptor Signaling. ACS Pharmacol Transl Sci. 2019 Jan 11;2(1):31-51. doi: 10.1021/acsptsci.8b00056. , eCollection 2019 Feb 8. PMID:32219215 doi:http://dx.doi.org/10.1021/acsptsci.8b00056
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