7um4: Difference between revisions
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==Crystal structure of inactive 5-HT5AR in complex with AS2674723== | |||
<StructureSection load='7um4' size='340' side='right'caption='[[7um4]], [[Resolution|resolution]] 2.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7um4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UM4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UM4 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=NN6:~{N}-[bis(azanyl)methylidene]-5-fluoranyl-8-[2,4,6-tris(fluoranyl)phenyl]-3,4-dihydro-1~{H}-isoquinoline-2-carboxamide'>NN6</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=7um4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7um4 OCA], [https://pdbe.org/7um4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7um4 RCSB], [https://www.ebi.ac.uk/pdbsum/7um4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7um4 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/5HT5A_HUMAN 5HT5A_HUMAN] G-protein coupled receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen (PubMed:35610220, PubMed:35835867, PubMed:9865521). Also functions as a receptor for ergot alkaloid derivatives and other psychoactive substances (PubMed:35835867). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:35610220, PubMed:35835867, PubMed:9865521). HTR5A is coupled to G(i)/G(o) G alpha proteins and mediates inhibitory neurotransmission: signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores (PubMed:35610220, PubMed:35835867, PubMed:9865521).<ref>PMID:35610220</ref> <ref>PMID:35835867</ref> <ref>PMID:9865521</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT)(5A) receptor (5-HT(5A)R) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 A) structures of human 5-HT(5A)Rs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HT(5A)R. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HT(5A)R. | |||
Inactive and active state structures template selective tools for the human 5-HT(5A) receptor.,Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL Nat Struct Mol Biol. 2022 Jul;29(7):677-687. doi: 10.1038/s41594-022-00796-6. , Epub 2022 Jul 14. PMID:35835867<ref>PMID:35835867</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7um4" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[5-hydroxytryptamine receptor 3D structures|5-hydroxytryptamine receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Roth BL]] | |||
[[Category: Zhang S]] | |||
Latest revision as of 14:37, 23 October 2024
Crystal structure of inactive 5-HT5AR in complex with AS2674723Crystal structure of inactive 5-HT5AR in complex with AS2674723
Structural highlights
Function5HT5A_HUMAN G-protein coupled receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen (PubMed:35610220, PubMed:35835867, PubMed:9865521). Also functions as a receptor for ergot alkaloid derivatives and other psychoactive substances (PubMed:35835867). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:35610220, PubMed:35835867, PubMed:9865521). HTR5A is coupled to G(i)/G(o) G alpha proteins and mediates inhibitory neurotransmission: signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores (PubMed:35610220, PubMed:35835867, PubMed:9865521).[1] [2] [3] Publication Abstract from PubMedSerotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT)(5A) receptor (5-HT(5A)R) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 A) structures of human 5-HT(5A)Rs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HT(5A)R. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HT(5A)R. Inactive and active state structures template selective tools for the human 5-HT(5A) receptor.,Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL Nat Struct Mol Biol. 2022 Jul;29(7):677-687. doi: 10.1038/s41594-022-00796-6. , Epub 2022 Jul 14. PMID:35835867[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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