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==== | ==Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist== | ||
<StructureSection load='7ld4' size='340' side='right'caption='[[7ld4]]' scene=''> | <StructureSection load='7ld4' size='340' side='right'caption='[[7ld4]], [[Resolution|resolution]] 3.30Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7ld4]] is a 4 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=7LD4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LD4 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=7ld4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ld4 OCA], [https://pdbe.org/7ld4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ld4 RCSB], [https://www.ebi.ac.uk/pdbsum/7ld4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ld4 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]] 3.3Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADN:ADENOSINE'>ADN</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=7ld4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ld4 OCA], [https://pdbe.org/7ld4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ld4 RCSB], [https://www.ebi.ac.uk/pdbsum/7ld4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ld4 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/GNAI2_HUMAN GNAI2_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. May play a role in cell division.<ref>PMID:17635935</ref> Isoform sGi2: Regulates the cell surface density of dopamine receptors DRD2 by sequestrating them as an intracellular pool.<ref>PMID:17550964</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The adenosine A(1) receptor (A(1)R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain(1,2). However, development of analgesic orthosteric A(1)R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects(3). Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A(1)R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A(1)R co-bound to adenosine, MIPS521 and a G(i2) heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts. | |||
Positive allosteric mechanisms of adenosine A(1) receptor-mediated analgesia.,Draper-Joyce CJ, Bhola R, Wang J, Bhattarai A, Nguyen ATN, Cowie-Kent I, O'Sullivan K, Chia LY, Venugopal H, Valant C, Thal DM, Wootten D, Panel N, Carlsson J, Christie MJ, White PJ, Scammells P, May LT, Sexton PM, Danev R, Miao Y, Glukhova A, Imlach WL, Christopoulos A Nature. 2021 Sep;597(7877):571-576. doi: 10.1038/s41586-021-03897-2. Epub 2021 , Sep 8. PMID:34497422<ref>PMID:34497422</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7ld4" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Muscarinic acetylcholine receptor|Muscarinic acetylcholine receptor]] | |||
*[[Transducin 3D structures|Transducin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Christopoulos A]] | ||
[[Category: Danev R]] | |||
[[Category: Draper-Joyce CJ]] | |||
[[Category: Glukhova A]] | |||
[[Category: Thal DM]] | |||
Latest revision as of 16:41, 6 November 2024
Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonistCryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist
Structural highlights
FunctionGNAI2_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. May play a role in cell division.[1] Isoform sGi2: Regulates the cell surface density of dopamine receptors DRD2 by sequestrating them as an intracellular pool.[2] Publication Abstract from PubMedThe adenosine A(1) receptor (A(1)R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain(1,2). However, development of analgesic orthosteric A(1)R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects(3). Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A(1)R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A(1)R co-bound to adenosine, MIPS521 and a G(i2) heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts. Positive allosteric mechanisms of adenosine A(1) receptor-mediated analgesia.,Draper-Joyce CJ, Bhola R, Wang J, Bhattarai A, Nguyen ATN, Cowie-Kent I, O'Sullivan K, Chia LY, Venugopal H, Valant C, Thal DM, Wootten D, Panel N, Carlsson J, Christie MJ, White PJ, Scammells P, May LT, Sexton PM, Danev R, Miao Y, Glukhova A, Imlach WL, Christopoulos A Nature. 2021 Sep;597(7877):571-576. doi: 10.1038/s41586-021-03897-2. Epub 2021 , Sep 8. PMID:34497422[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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