8hs2: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8hs2]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Rattus Rattus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8HS2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8HS2 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8hs2]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Rattus Rattus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8HS2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8HS2 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=8hs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8hs2 OCA], [https://pdbe.org/8hs2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8hs2 RCSB], [https://www.ebi.ac.uk/pdbsum/8hs2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8hs2 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]] 3.08Å</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=8hs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8hs2 OCA], [https://pdbe.org/8hs2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8hs2 RCSB], [https://www.ebi.ac.uk/pdbsum/8hs2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8hs2 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function.[https://www.uniprot.org/uniprot/GPR20_HUMAN GPR20_HUMAN] Orphan receptor with constitutive G(i) signaling activity that activate cyclic AMP.<ref>PMID:18347022</ref> | [https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function.[https://www.uniprot.org/uniprot/GPR20_HUMAN GPR20_HUMAN] Orphan receptor with constitutive G(i) signaling activity that activate cyclic AMP.<ref>PMID:18347022</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
GPR20 is a class-A orphan G protein-coupled receptor (GPCR) and a potential therapeutic target for gastrointestinal stromal tumors (GIST) owing to its differentially high expression. An antibody-drug conjugate (ADC) containing a GPR20-binding antibody (Ab046) was recently developed in clinical trials for GIST treatment. GPR20 constitutively activates Gi proteins in the absence of any known ligand, but it remains obscure how this high basal activity is achieved. Here we report three cryo-EM structures of human GPR20 complexes including Gi-coupled GPR20 in the absence or presence of the Fab fragment of Ab046 and Gi-free GPR20. Remarkably, the structures demonstrate a uniquely folded N-terminal helix capping onto the transmembrane domain and our mutagenesis study suggests a key role of this cap region in stimulating the basal activity of GPR20. We also uncover the molecular interactions between GPR20 and Ab046, which may enable the design of tool antibodies with enhanced affinity or new functionality for GPR20. Furthermore, we report the orthosteric pocket occupied by an unassigned density which might be essential for exploring opportunities for deorphanization. | |||
The activation mechanism and antibody binding mode for orphan GPR20.,Lin X, Jiang S, Wu Y, Wei X, Han GW, Wu L, Liu J, Chen B, Zhang Z, Zhao S, Cherezov V, Xu F Cell Discov. 2023 Feb 28;9(1):23. doi: 10.1038/s41421-023-00520-8. PMID:36849514<ref>PMID:36849514</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 8hs2" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 17:39, 6 November 2024
Orphan GPR20 in complex with Fab046Orphan GPR20 in complex with Fab046
Structural highlights
FunctionC562_ECOLX Electron-transport protein of unknown function.GPR20_HUMAN Orphan receptor with constitutive G(i) signaling activity that activate cyclic AMP.[1] Publication Abstract from PubMedGPR20 is a class-A orphan G protein-coupled receptor (GPCR) and a potential therapeutic target for gastrointestinal stromal tumors (GIST) owing to its differentially high expression. An antibody-drug conjugate (ADC) containing a GPR20-binding antibody (Ab046) was recently developed in clinical trials for GIST treatment. GPR20 constitutively activates Gi proteins in the absence of any known ligand, but it remains obscure how this high basal activity is achieved. Here we report three cryo-EM structures of human GPR20 complexes including Gi-coupled GPR20 in the absence or presence of the Fab fragment of Ab046 and Gi-free GPR20. Remarkably, the structures demonstrate a uniquely folded N-terminal helix capping onto the transmembrane domain and our mutagenesis study suggests a key role of this cap region in stimulating the basal activity of GPR20. We also uncover the molecular interactions between GPR20 and Ab046, which may enable the design of tool antibodies with enhanced affinity or new functionality for GPR20. Furthermore, we report the orthosteric pocket occupied by an unassigned density which might be essential for exploring opportunities for deorphanization. The activation mechanism and antibody binding mode for orphan GPR20.,Lin X, Jiang S, Wu Y, Wei X, Han GW, Wu L, Liu J, Chen B, Zhang Z, Zhao S, Cherezov V, Xu F Cell Discov. 2023 Feb 28;9(1):23. doi: 10.1038/s41421-023-00520-8. PMID:36849514[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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