View source for 7ept


==Structural basis for the tethered peptide activation of adhesion GPCRs==
<StructureSection load='7ept' size='340' side='right'caption='[[7ept]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7ept]] 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=7EPT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EPT FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=7ept FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ept OCA], [https://pdbe.org/7ept PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ept RCSB], [https://www.ebi.ac.uk/pdbsum/7ept PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ept ProSAT]</span></td></tr>
</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 ==
Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes(1-6). Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence(7-12). Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with G(s): GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an alpha-helical-bulge-beta-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W(6.53) and the constitution of a hydrogen-bond network formed by Q(7.49)/Y(7.49) and the P(6.47)/V(6.47)phiphiG(6.50) motif (phi indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and G(s) coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common G(s)-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with G(s). Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their G(s) coupling.

Structural basis for the tethered peptide activation of adhesion GPCRs.,Ping YQ, Xiao P, Yang F, Zhao RJ, Guo SC, Yan X, Wu X, Zhang C, Lu Y, Zhao F, Zhou F, Xi YT, Yin W, Liu FZ, He DF, Zhang DL, Zhu ZL, Jiang Y, Du L, Feng SQ, Schoneberg T, Liebscher I, Xu HE, Sun JP Nature. 2022 Apr;604(7907):763-770. doi: 10.1038/s41586-022-04619-y. Epub 2022 , Apr 13. PMID:35418678<ref>PMID:35418678</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7ept" style="background-color:#fffaf0;"></div>

==See Also==
*[[Transducin 3D structures|Transducin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Guo S-C]]
[[Category: Liebscher I]]
[[Category: Ping Y-Q]]
[[Category: Sun J-P]]
[[Category: Wu X]]
[[Category: Xiao P]]
[[Category: Xu HE]]
[[Category: Yan X]]
[[Category: Yang F]]
[[Category: Zhao R-J]]