8wc5: Difference between revisions
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==Cryo-EM structure of the TMA-bound mTAAR1-Gs complex== | |||
<StructureSection load='8wc5' size='340' side='right'caption='[[8wc5]], [[Resolution|resolution]] 3.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8wc5]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8WC5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8WC5 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]] 3.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TMA:TETRAMETHYLAMMONIUM+ION'>TMA</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=8wc5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8wc5 OCA], [https://pdbe.org/8wc5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8wc5 RCSB], [https://www.ebi.ac.uk/pdbsum/8wc5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8wc5 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.<ref>PMID:18611381</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 8wc5" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: Guo | <references/> | ||
[[Category: Li | __TOC__ | ||
[[Category: Yang | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Guo LL]] | |||
[[Category: Li Q]] | |||
[[Category: Rong NK]] | |||
[[Category: Sun JP]] | |||
[[Category: Yang F]] | |||
[[Category: Zhang MH]] | |||
Revision as of 02:16, 28 December 2023
Cryo-EM structure of the TMA-bound mTAAR1-Gs complexCryo-EM structure of the TMA-bound mTAAR1-Gs complex
Structural highlights
FunctionGBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[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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