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- EMDB-26598: CryoEM structure of Go-coupled 5-HT5AR in complex with Lisuride -

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Entry
Database: EMDB / ID: EMD-26598
TitleCryoEM structure of Go-coupled 5-HT5AR in complex with Lisuride
Map dataprimary map
Sample
  • Complex: Go-coupled 5-HT5AR complex
    • Complex: 5-hydroxytryptamine receptor 5A, miniGo protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
      • Protein or peptide: 5-hydroxytryptamine receptor 5A
      • Protein or peptide: miniGo protein
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: Single-chain variable fragment scFv16
      • Protein or peptide: Single-chain variable fragment scFv16
  • Ligand: N,N-diethyl-N'-[(8alpha)-6-methyl-9,10-didehydroergolin-8-yl]urea
KeywordsGPCR / Lisuride / active state / MEMBRANE PROTEIN / 5-HT5AR / HTR5A / Go
Function / homology
Function and homology information


adenylate cyclase-inhibiting serotonin receptor signaling pathway / Serotonin receptors / serotonin binding / G protein-coupled serotonin receptor activity / postsynaptic specialization membrane / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hippocampus development / Olfactory Signaling Pathway / Activation of the phototransduction cascade ...adenylate cyclase-inhibiting serotonin receptor signaling pathway / Serotonin receptors / serotonin binding / G protein-coupled serotonin receptor activity / postsynaptic specialization membrane / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hippocampus development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / 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 / 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 / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / response to estradiol / 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 / chemical synaptic transmission / G alpha (q) signalling events / perikaryon / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / dendrite / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
5-Hydroxytryptamine 5A receptor / 5-hydroxytryptamine receptor family / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit ...5-Hydroxytryptamine 5A receptor / 5-hydroxytryptamine receptor family / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
5-hydroxytryptamine receptor 5A / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.79 Å
AuthorsZhang S / Fay JF / Roth BL
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)RO1MH112205 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)U24DK1169195 United States
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Inactive and active state structures template selective tools for the human 5-HT receptor.
Authors: Shicheng Zhang / He Chen / Chengwei Zhang / Ying Yang / Petr Popov / Jing Liu / Brian E Krumm / Can Cao / Kuglae Kim / Yan Xiong / Vsevolod Katritch / Brian K Shoichet / Jian Jin / Jonathan ...Authors: Shicheng Zhang / He Chen / Chengwei Zhang / Ying Yang / Petr Popov / Jing Liu / Brian E Krumm / Can Cao / Kuglae Kim / Yan Xiong / Vsevolod Katritch / Brian K Shoichet / Jian Jin / Jonathan F Fay / Bryan L Roth /
Abstract: Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 ...Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT) receptor (5-HTR) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 Å) structures of human 5-HTRs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HTR. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HTR.
History
DepositionApr 6, 2022-
Header (metadata) releaseJul 20, 2022-
Map releaseJul 20, 2022-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26598.png

Downloads & links

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Map

FileDownload / File: emd_26598.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationprimary map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.91 Å/pix.
x 256 pix.
= 232.96 Å		0.91 Å/pix.
x 256 pix.
= 232.96 Å		0.91 Å/pix.
x 256 pix.
= 232.96 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.91 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.128
Minimum - Maximum-0.03067494 - 1.7235757
Average (Standard dev.)0.0015849082 (±0.026917554)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 232.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_26598_msk_1.map
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Half map: half map A

Fileemd_26598_half_map_1.map
Annotationhalf map A
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Half map: half map B

Fileemd_26598_half_map_2.map
Annotationhalf map B
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Sample components

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Entire : Go-coupled 5-HT5AR complex

EntireName: Go-coupled 5-HT5AR complex
Components
  • Complex: Go-coupled 5-HT5AR complex
    • Complex: 5-hydroxytryptamine receptor 5A, miniGo protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
      • Protein or peptide: 5-hydroxytryptamine receptor 5A
      • Protein or peptide: miniGo protein
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: Single-chain variable fragment scFv16
      • Protein or peptide: Single-chain variable fragment scFv16
  • Ligand: N,N-diethyl-N'-[(8alpha)-6-methyl-9,10-didehydroergolin-8-yl]urea

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Supramolecule #1: Go-coupled 5-HT5AR complex

SupramoleculeName: Go-coupled 5-HT5AR complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5

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Supramolecule #2: 5-hydroxytryptamine receptor 5A, miniGo protein, Guanine nucleoti...

SupramoleculeName: 5-hydroxytryptamine receptor 5A, miniGo protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Single-chain variable fragment scFv16

SupramoleculeName: Single-chain variable fragment scFv16 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #5
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: 5-hydroxytryptamine receptor 5A

MacromoleculeName: 5-hydroxytryptamine receptor 5A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.884168 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SSPLLSVFGV LILTLLGFLV AATFAWNLLV LATILRVRTF HRVPHNLVAS MAVSDVLVAA LVMPLSLVHE LSGRRWQLGR RLCQLWIAC DVLCCTASIW NVTAIALDRY WSITRPMEYT LRTRKCVSNV MIALTWALSA VISLAPLLFG WGETYSEGSE E CQVSREPS ...String:
SSPLLSVFGV LILTLLGFLV AATFAWNLLV LATILRVRTF HRVPHNLVAS MAVSDVLVAA LVMPLSLVHE LSGRRWQLGR RLCQLWIAC DVLCCTASIW NVTAIALDRY WSITRPMEYT LRTRKCVSNV MIALTWALSA VISLAPLLFG WGETYSEGSE E CQVSREPS YAVFSTVGAF YLPLCVVLFV YWKIYKAAKF RVGSRKTNSV SPISEAVEVK DSAKQPQMVF TVRHATVTFQ PE GDTWREQ KEQRAALMVG ILIGVFVLCW IPFFLTELIS PLCSCDIPAI WKSIFLWLGY SNSFFNPLIY TAFNKNYNSA FKN FFSRQH

UniProtKB: 5-hydroxytryptamine receptor 5A

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Macromolecule #2: miniGo protein

MacromoleculeName: miniGo protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.159777 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: TLSAEDKAAV ERSKMIEKNL KEDGISAAKD VKLLLLGADN SGKSTIVKQM KIIHGGSGGS GGTTGIVETH FTFKNLHFRL FDVGGQRSE RKKWIHCFED VTAIIFCVDL SDYNRMHESL MLFDSICNNK FFIDTSIILF LNKKDLFGEK IKKSPLTICF P EYTGPNTY ...String:
TLSAEDKAAV ERSKMIEKNL KEDGISAAKD VKLLLLGADN SGKSTIVKQM KIIHGGSGGS GGTTGIVETH FTFKNLHFRL FDVGGQRSE RKKWIHCFED VTAIIFCVDL SDYNRMHESL MLFDSICNNK FFIDTSIILF LNKKDLFGEK IKKSPLTICF P EYTGPNTY EDAAAYIQAQ FESKNRSPNK EIYCHMTCAT DTNNAQVIFD AVTDIIIANN LRGCGLY

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.285734 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW ...String:
SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NAICFFPNGN AF ATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGHDNRVSCL GVT DDGMAV ATGSWDSFLK IWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #5: Single-chain variable fragment scFv16

MacromoleculeName: Single-chain variable fragment scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.679721 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAA

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Macromolecule #6: N,N-diethyl-N'-[(8alpha)-6-methyl-9,10-didehydroergolin-8-yl]urea

MacromoleculeName: N,N-diethyl-N'-[(8alpha)-6-methyl-9,10-didehydroergolin-8-yl]urea
type: ligand / ID: 6 / Number of copies: 1 / Formula: H8G
Molecular weightTheoretical: 338.447 Da
Chemical component information

ChemComp-H8G:
N,N-diethyl-N'-[(8alpha)-6-methyl-9,10-didehydroergolin-8-yl]urea / medication*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TECNAI 10
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 43.8 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.211 µm / Nominal defocus min: 0.14300000000000002 µm

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.79 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 226599
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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