7v6a: Difference between revisions
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==Cry-EM structure of M4-c110-G protein complex== | ==Cry-EM structure of M4-c110-G protein complex== | ||
<StructureSection load='7v6a' size='340' side='right'caption='[[7v6a]]' scene=''> | <StructureSection load='7v6a' size='340' side='right'caption='[[7v6a]], [[Resolution|resolution]] 3.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7V6A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V6A FirstGlance]. <br> | <table><tr><td colspan='2'>[[7v6a]] is a 5 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=7V6A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7V6A 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=7v6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v6a OCA], [https://pdbe.org/7v6a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v6a RCSB], [https://www.ebi.ac.uk/pdbsum/7v6a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v6a ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5XI:methyl+4-[4-(3-methyl-2-oxidanylidene-benzimidazol-1-yl)piperidin-1-yl]piperidine-1-carboxylate'>5XI</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=7v6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7v6a OCA], [https://pdbe.org/7v6a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7v6a RCSB], [https://www.ebi.ac.uk/pdbsum/7v6a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7v6a ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/GNAI1_HUMAN GNAI1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.<ref>PMID:17635935</ref> <ref>PMID:17264214</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Muscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer's disease and schizophrenia. However, the lack of understanding on M4R's activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-G(i) complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-G(i) structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes. | |||
The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.,Wang J, Wu M, Chen Z, Wu L, Wang T, Cao D, Wang H, Liu S, Xu Y, Li F, Liu J, Chen N, Zhao S, Cheng J, Wang S, Hua T Nat Commun. 2022 May 23;13(1):2855. doi: 10.1038/s41467-022-30595-y. PMID:35606397<ref>PMID:35606397</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7v6a" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Transducin 3D structures|Transducin 3D structures]] | *[[Transducin 3D structures|Transducin 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hua T]] | [[Category: Hua T]] | ||
Revision as of 13:26, 24 November 2022
Cry-EM structure of M4-c110-G protein complexCry-EM structure of M4-c110-G protein complex
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedMuscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer's disease and schizophrenia. However, the lack of understanding on M4R's activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-G(i) complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-G(i) structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes. The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.,Wang J, Wu M, Chen Z, Wu L, Wang T, Cao D, Wang H, Liu S, Xu Y, Li F, Liu J, Chen N, Zhao S, Cheng J, Wang S, Hua T Nat Commun. 2022 May 23;13(1):2855. doi: 10.1038/s41467-022-30595-y. PMID:35606397[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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