+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-36402 | |||||||||
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Title | Ulotaront(SEP-363856)-bound hTAAR1-Gs protein complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Complex / Agonist / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information Amine ligand-binding receptors / trace-amine receptor activity / PKA activation in glucagon signalling / hair follicle placode formation / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / Hedgehog 'off' state ...Amine ligand-binding receptors / trace-amine receptor activity / PKA activation in glucagon signalling / hair follicle placode formation / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / Hedgehog 'off' state / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / trans-Golgi network membrane / G protein-coupled receptor activity / electron transport chain / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / bone development / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / 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 / cognition / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / platelet aggregation / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / 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 / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / periplasmic space / electron transfer activity / iron ion binding / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / heme binding / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.52 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_36402.map.gz | 59.7 MB | EMDB map data format | |
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Header (meta data) | emd-36402-v30.xml emd-36402.xml | 20.5 KB 20.5 KB | Display Display | EMDB header |
Images | emd_36402.png | 75.1 KB | ||
Filedesc metadata | emd-36402.cif.gz | 6.7 KB | ||
Others | emd_36402_half_map_1.map.gz emd_36402_half_map_2.map.gz | 59.3 MB 59.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-36402 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36402 | HTTPS FTP |
-Validation report
Summary document | emd_36402_validation.pdf.gz | 1.1 MB | Display | EMDB validaton report |
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Full document | emd_36402_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | emd_36402_validation.xml.gz | 12.3 KB | Display | |
Data in CIF | emd_36402_validation.cif.gz | 14.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36402 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36402 | HTTPS FTP |
-Related structure data
Related structure data | 8jloMC 8jljC 8jlkC 8jlnC 8jlpC 8jlqC 8jlrC 8jsoC 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_36402.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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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: #2
File | emd_36402_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_36402_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : hTAAR1-bound SEP363856 in complex with Gs heterotrimer
Entire | Name: hTAAR1-bound SEP363856 in complex with Gs heterotrimer |
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Components |
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-Supramolecule #1: hTAAR1-bound SEP363856 in complex with Gs heterotrimer
Supramolecule | Name: hTAAR1-bound SEP363856 in complex with Gs heterotrimer type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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-Supramolecule #2: Gs heterotrimer
Supramolecule | Name: Gs heterotrimer / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2, #4 |
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Source (natural) | Organism: Homo sapiens (human) |
-Supramolecule #3: SEP-bound hTAAR1
Supramolecule | Name: SEP-bound hTAAR1 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Macromolecule | Name: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 45.699434 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCS VDTENIRRVF NDCRDIIQRM HLRQYELL UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 39.141793 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MHHHHLEVLF QGPGSSGSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSA SQDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT G YLSCCRFL ...String: MHHHHLEVLF QGPGSSGSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSA SQDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT G YLSCCRFL DDNQIVTSSG DTTCALWDIE TGQQTTTFTG HTGDVMSLSL APDTRLFVSG ACDASAKLWD VREGMCRQTF TG HESDINA ICFFPNGNAF ATGSDDATCR LFDLRADQEL MTYSHDNIIC GITSVSFSKS GRLLLAGYDD FNCNVWDALK ADR AGVLAG HDNRVSCLGV TDDGMAVATG SWDSFLKIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #3: Soluble cytochrome b562,Trace amine-associated receptor 1
Macromolecule | Name: Soluble cytochrome b562,Trace amine-associated receptor 1 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 54.128133 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: DYKDDDDKHH HHHHHHHHEN LYFQGADLED NWETLNDNLK VIEKADNAAQ VKDALTKMRA AALDAQKATP PKLEDKSPDS PEMKDFRHG FDILVGQIDD ALKLANEGKV KEAQAAAEQL KTTRNAYIQK YLMMPFCHNI INISCVKNNW SNDVRASLYS L MVLIILTT ...String: DYKDDDDKHH HHHHHHHHEN LYFQGADLED NWETLNDNLK VIEKADNAAQ VKDALTKMRA AALDAQKATP PKLEDKSPDS PEMKDFRHG FDILVGQIDD ALKLANEGKV KEAQAAAEQL KTTRNAYIQK YLMMPFCHNI INISCVKNNW SNDVRASLYS L MVLIILTT LVGNLIVIVS ISHFKQLHTP TNWLIHSMAT VDFLLGCLVM PYSMVRSAEH CWYFGEVFCK IHTSTDIMLS SA SIFHLSF ISIDRYYAVC DPLRYKAKMN ILVICVMIFI SWSVPAVFAF GMIFLELNFK GAEEIYYKHV HCRGGCSVFF SKI SGVLTF MTSFYIPGSI MLCVYYRIYL IAKEQARLIS DANQKLQIGL EMKNGISQSK ERKAVKTLGI VMGVFLICWC PFFI CTVMD PFLHYIIPPT LNDVLIWFGY LNSTFNPMVY AFFYPWFRKA LKMMLFGKIF QKDSSRCKLF LELSS UniProtKB: Soluble cytochrome b562, Trace amine-associated receptor 1 |
-Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #5: 1-[(7~{S})-5,7-dihydro-4~{H}-thieno[2,3-c]pyran-7-yl]-~{N}-methyl...
Macromolecule | Name: 1-[(7~{S})-5,7-dihydro-4~{H}-thieno[2,3-c]pyran-7-yl]-~{N}-methyl-methanamine type: ligand / ID: 5 / Number of copies: 1 / Formula: UJL |
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Molecular weight | Theoretical: 183.271 Da |
Chemical component information | ChemComp-UJL: |
-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: 66.0 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: 3.52 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 4432355 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |