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Yorodumi- EMDB-36626: Ulotaront(SEP-363856)-bound Serotonin 1A (5-HT1A) receptor-Gi complex -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-36626 | |||||||||
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Title | Ulotaront(SEP-363856)-bound Serotonin 1A (5-HT1A) receptor-Gi complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Complex / Agonist / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / regulation of behavior / Serotonin receptors / receptor-receptor interaction / serotonin receptor signaling pathway / regulation of dopamine metabolic process / serotonin metabolic process / serotonin binding ...regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / regulation of behavior / Serotonin receptors / receptor-receptor interaction / serotonin receptor signaling pathway / regulation of dopamine metabolic process / serotonin metabolic process / serotonin binding / G protein-coupled serotonin receptor activity / gamma-aminobutyric acid signaling pathway / exploration behavior / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / behavioral fear response / T cell migration / regulation of vasoconstriction / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Regulation of insulin secretion / G protein-coupled receptor binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / response to peptide hormone / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / midbody / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / chemical synaptic transmission / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / centrosome / dendrite / positive regulation of cell population proliferation / synapse / GTP binding / protein-containing complex binding / nucleolus / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.65 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_36626.map.gz | 59.7 MB | EMDB map data format | |
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Header (meta data) | emd-36626-v30.xml emd-36626.xml | 21.5 KB 21.5 KB | Display Display | EMDB header |
Images | emd_36626.png | 60.2 KB | ||
Filedesc metadata | emd-36626.cif.gz | 6.7 KB | ||
Others | emd_36626_half_map_1.map.gz emd_36626_half_map_2.map.gz | 59.5 MB 59.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-36626 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36626 | HTTPS FTP |
-Validation report
Summary document | emd_36626_validation.pdf.gz | 932 KB | Display | EMDB validaton report |
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Full document | emd_36626_full_validation.pdf.gz | 931.5 KB | Display | |
Data in XML | emd_36626_validation.xml.gz | 12.3 KB | Display | |
Data in CIF | emd_36626_validation.cif.gz | 14.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36626 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36626 | HTTPS FTP |
-Related structure data
Related structure data | 8jspMC 8jljC 8jlkC 8jlnC 8jloC 8jlpC 8jlqC 8jlrC 8jsoC 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_36626.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: 0.92 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_36626_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_36626_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : hTAAR1-bound T1AM in complex with Gs heterotrimer
Entire | Name: hTAAR1-bound T1AM in complex with Gs heterotrimer |
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Components |
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-Supramolecule #1: hTAAR1-bound T1AM in complex with Gs heterotrimer
Supramolecule | Name: hTAAR1-bound T1AM in complex with Gs heterotrimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2, #4-#5, #3 |
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-Supramolecule #2: 5HT1A in complex with Gi heterotrimer
Supramolecule | Name: 5HT1A in complex with Gi heterotrimer / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2, #4-#5 |
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Source (natural) | Organism: Homo sapiens (human) |
-Supramolecule #3: scFv16
Supramolecule | Name: scFv16 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3 |
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Source (natural) | Organism: Mus musculus (house mouse) |
-Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 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: 40.12266 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: TLSAEDKAAV ERSKMIDRNL REDGEKAARE VKLLLLGAGE SGKNTIVKQM KIIHEAGYSE EECKQYKAVV YSNTIQSIIA IIRAMGRLK IDFGDSARAD DARQLFVLAG AAEEGFMTAE LAGVIKRLWK DSGVQACFNR SREYQLNDSA AYYLNDLDRI A QPNYIPTQ ...String: TLSAEDKAAV ERSKMIDRNL REDGEKAARE VKLLLLGAGE SGKNTIVKQM KIIHEAGYSE EECKQYKAVV YSNTIQSIIA IIRAMGRLK IDFGDSARAD DARQLFVLAG AAEEGFMTAE LAGVIKRLWK DSGVQACFNR SREYQLNDSA AYYLNDLDRI A QPNYIPTQ QDVLRTRVKT TGIVETHFTF KDLHFKMFDV GAQRSERKKW IHCFEGVTAI IFCVALSDYD LVLAEDEEMN RM HASMKLF DSICNNKWFT DTSIILFLNK KDLFEEKIKK SPLTICYPEY AGSNTYEEAA AYIQCQFEDL NKRKDTKEIY THF TCSTDT KNVQFVFDAV TDVIIKNNLK DCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-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: 35.985395 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLIIW DSYTTNKVHA IPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF LDDNQIVTSS GDTTCALWDI E TGQQTTTF ...String: QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLIIW DSYTTNKVHA IPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF LDDNQIVTSS GDTTCALWDI E TGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TFTGHESDIN AICFFPNGNA FATGSDDATC RL FDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKADRAGVLA GHDNRVSCLG VTDDGMAVAT GSW DSFLKI WN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #3: ScFv16
Macromolecule | Name: ScFv16 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 26.59466 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG SGGGSSDIVM TQATSSVPVT PGESVSISCR S SKSLLHSN ...String: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG SGGGSSDIVM TQATSSVPVT PGESVSISCR S SKSLLHSN GNTYLYWFLQ RPGQSPQLLI YRMSNLASGV PDRFSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GA GTKLELK AAA |
-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: 4.990752 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: QLKMEANIDR IKVSKAAADL MAYCEAHAKE DPLLTPVPAS ENPFR UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #5: 5-hydroxytryptamine receptor 1A
Macromolecule | Name: 5-hydroxytryptamine receptor 1A / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 42.001121 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: YQVITSLLLG TLIFCAVLGN ACVVAAIALE RSLQNVANYL IGSLAVTDLM VSVLVLPMAA LYQVLNKWTL GQVTCDLFIA LDVLCCTSS IWHLCAIALD RYWAITDPID YVNKRTPRRA AALISLTWLI GFLISIPPML GWRTPEDRSD PDACTISKDH G YTIYSTFG ...String: YQVITSLLLG TLIFCAVLGN ACVVAAIALE RSLQNVANYL IGSLAVTDLM VSVLVLPMAA LYQVLNKWTL GQVTCDLFIA LDVLCCTSS IWHLCAIALD RYWAITDPID YVNKRTPRRA AALISLTWLI GFLISIPPML GWRTPEDRSD PDACTISKDH G YTIYSTFG AFYIPLLLML VLYGRIFRAA RFRIRKTVKK VEKTGADTRH GASPAPQPKK SVNGESGSRN WRLGVESKAG GA LCANGAV RQGDDGAALE VIEVHRVGNS KEHLPLPSEA GPTPCAPASF ERKNERNAEA KRKMALARER KTVKTLGIIM GTF ILCWLP FFIVALVLPF CESSCHMPTL LGAIINWLGY SNSLLNPVIY AYFNKDFQNA FKKII UniProtKB: 5-hydroxytryptamine receptor 1A |
-Macromolecule #6: 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: 6 Details: This is a sythentetic compound that similar with amino acid. 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 K3 (6k x 4k) / Average electron dose: 60.0 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: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 313570 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |