+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-36625 | |||||||||
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Title | AMPH-bound hTAAR1-Gs protein complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Complex / Agonist / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex | |||||||||
Function / homology | Function and homology information G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Prostacyclin signalling through prostacyclin receptor / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Amine ligand-binding receptors / G beta:gamma signalling through BTK / Adrenaline,noradrenaline inhibits insulin secretion ...G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Prostacyclin signalling through prostacyclin receptor / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Amine ligand-binding receptors / G beta:gamma signalling through BTK / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thromboxane signalling through TP receptor / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Ca2+ pathway / G alpha (s) signalling events / trace-amine receptor activity / G alpha (q) signalling events / Extra-nuclear estrogen signaling / G alpha (12/13) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / GPER1 signaling / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / G protein-coupled receptor activity / electron transport chain / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / periplasmic space / electron transfer activity / iron ion binding / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / heme binding / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
Authors | Xu Z / Guo LL / Zhao C / Shen SY / Sun JP / Shao ZH | |||||||||
Funding support | China, 1 items
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Citation | Journal: Nature / Year: 2023 Title: Ligand recognition and G-protein coupling of trace amine receptor TAAR1. Authors: Zheng Xu / Lulu Guo / Jingjing Yu / Siyuan Shen / Chao Wu / Weifeng Zhang / Chang Zhao / Yue Deng / Xiaowen Tian / Yuying Feng / Hanlin Hou / Lantian Su / Hongshuang Wang / Shuo Guo / Heli ...Authors: Zheng Xu / Lulu Guo / Jingjing Yu / Siyuan Shen / Chao Wu / Weifeng Zhang / Chang Zhao / Yue Deng / Xiaowen Tian / Yuying Feng / Hanlin Hou / Lantian Su / Hongshuang Wang / Shuo Guo / Heli Wang / Kexin Wang / Peipei Chen / Jie Zhao / Xiaoyu Zhang / Xihao Yong / Lin Cheng / Lunxu Liu / Shengyong Yang / Fan Yang / Xiaohui Wang / Xiao Yu / Yunfei Xu / Jin-Peng Sun / Wei Yan / Zhenhua Shao / Abstract: Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse endogenous trace amines and ...Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HTR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_36625.map.gz | 59.7 MB | EMDB map data format | |
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Header (meta data) | emd-36625-v30.xml emd-36625.xml | 21.8 KB 21.8 KB | Display Display | EMDB header |
Images | emd_36625.png | 57.6 KB | ||
Filedesc metadata | emd-36625.cif.gz | 6.8 KB | ||
Others | emd_36625_half_map_1.map.gz emd_36625_half_map_2.map.gz | 59.3 MB 59.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-36625 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36625 | HTTPS FTP |
-Validation report
Summary document | emd_36625_validation.pdf.gz | 858.5 KB | Display | EMDB validaton report |
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Full document | emd_36625_full_validation.pdf.gz | 858.1 KB | Display | |
Data in XML | emd_36625_validation.xml.gz | 12.2 KB | Display | |
Data in CIF | emd_36625_validation.cif.gz | 14.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36625 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36625 | HTTPS FTP |
-Related structure data
Related structure data | 8jsoMC 8jljC 8jlkC 8jlnC 8jloC 8jlpC 8jlqC 8jlrC 8jspC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_36625.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.85 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_36625_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_36625_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : hTAAR1-bound amphetamine in complex with Gs heterotrimer
+Supramolecule #1: hTAAR1-bound amphetamine in complex with Gs heterotrimer
+Supramolecule #2: Gs heterotrimer
+Supramolecule #3: scFV16
+Supramolecule #4: amphetamine-bound hTAAR1
+Macromolecule #1: mGs
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Soluble cytochrome b562,Trace amine-associated receptor 1
+Macromolecule #4: ScFv16
+Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #6: (2S)-1-phenylpropan-2-amine
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 57.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 704271 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |