8wcc: Difference between revisions
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The | ==Cryo-EM structure of the CHA-bound mTAAR1 complex== | ||
<StructureSection load='8wcc' size='340' side='right'caption='[[8wcc]], [[Resolution|resolution]] 3.04Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8wcc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8WCC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8WCC 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]] 3.04Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HAI:CYCLOHEXYLAMMONIUM+ION'>HAI</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=8wcc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8wcc OCA], [https://pdbe.org/8wcc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8wcc RCSB], [https://www.ebi.ac.uk/pdbsum/8wcc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8wcc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TAAR1_MOUSE TAAR1_MOUSE] Receptor for trace amines, including beta-phenylethylamine (b-PEA), p-tyramine (p-TYR), octopamine and tryptamine, with highest affinity for b-PEA and p-TYR. Unresponsive to classical biogenic amines, such as epinephrine and histamine and only partially activated by dopamine and serotonin. Trace amines are biogenic amines present in very low levels in mammalian tissues. Although some trace amines have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Trace amines are likely to be involved in a variety of physiological functions that have yet to be fully understood. The signal transduced by this receptor is mediated by the G(s)-class of G-proteins which activate adenylate cyclase.<ref>PMID:15718104</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D(3.32) for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design. | |||
Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.,Shang P, Rong N, Jiang JJ, Cheng J, Zhang MH, Kang D, Qi L, Guo L, Yang GM, Liu Q, Zhou Z, Li XB, Zhu KK, Meng QB, Han X, Yan W, Kong Y, Yang L, Wang X, Lei D, Feng X, Liu X, Yu X, Wang Y, Li Q, Shao ZH, Yang F, Sun JP Cell. 2023 Nov 22;186(24):5347-5362.e24. doi: 10.1016/j.cell.2023.10.014. Epub , 2023 Nov 13. PMID:37963465<ref>PMID:37963465</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8wcc" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: Li | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Mus musculus]] | |||
[[Category: Guo LL]] | |||
[[Category: Li Q]] | |||
[[Category: Rong NK]] | |||
[[Category: Sun JP]] | |||
[[Category: Yang F]] | |||
[[Category: Zhang MH]] | |||
Latest revision as of 02:17, 28 December 2023
Cryo-EM structure of the CHA-bound mTAAR1 complexCryo-EM structure of the CHA-bound mTAAR1 complex
Structural highlights
FunctionTAAR1_MOUSE Receptor for trace amines, including beta-phenylethylamine (b-PEA), p-tyramine (p-TYR), octopamine and tryptamine, with highest affinity for b-PEA and p-TYR. Unresponsive to classical biogenic amines, such as epinephrine and histamine and only partially activated by dopamine and serotonin. Trace amines are biogenic amines present in very low levels in mammalian tissues. Although some trace amines have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Trace amines are likely to be involved in a variety of physiological functions that have yet to be fully understood. The signal transduced by this receptor is mediated by the G(s)-class of G-proteins which activate adenylate cyclase.[1] Publication Abstract from PubMedTrace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D(3.32) for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design. Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.,Shang P, Rong N, Jiang JJ, Cheng J, Zhang MH, Kang D, Qi L, Guo L, Yang GM, Liu Q, Zhou Z, Li XB, Zhu KK, Meng QB, Han X, Yan W, Kong Y, Yang L, Wang X, Lei D, Feng X, Liu X, Yu X, Wang Y, Li Q, Shao ZH, Yang F, Sun JP Cell. 2023 Nov 22;186(24):5347-5362.e24. doi: 10.1016/j.cell.2023.10.014. Epub , 2023 Nov 13. PMID:37963465[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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