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- EMDB-30665: Cryo-EM structure of histamine H1 receptor Gq complex -

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Basic information

Entry
Database: EMDB / ID: EMD-30665
TitleCryo-EM structure of histamine H1 receptor Gq complex
Map data
Sample
  • Complex: GPCR/G-protein complex
    • Protein or peptide: Histamine H1 receptor
    • 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
    • Protein or peptide: Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: scFv16
  • Ligand: HISTAMINE
Keywordscomplex / MEMBRANE PROTEIN
Function / homology
Function and homology information


Histamine receptors / histamine receptor activity / cellular response to histamine / regulation of vascular permeability / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of vasoconstriction / visual learning / regulation of synaptic plasticity / memory / Olfactory Signaling Pathway ...Histamine receptors / histamine receptor activity / cellular response to histamine / regulation of vascular permeability / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of vasoconstriction / visual learning / regulation of synaptic plasticity / memory / 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 / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / 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 / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / G alpha (s) signalling events / chemical synaptic transmission / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / inflammatory response / lysosomal membrane / GTPase activity / dendrite / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Histamine H1 receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 ...Histamine H1 receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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
Histamine H1 receptor / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsHe Y / Xia R
CitationJournal: Nat Commun / Year: 2021
Title: Cryo-EM structure of the human histamine H receptor/G complex.
Authors: Ruixue Xia / Na Wang / Zhenmei Xu / Yang Lu / Jing Song / Anqi Zhang / Changyou Guo / Yuanzheng He /
Abstract: Histamine receptors play important roles in various pathophysiological conditions and are effective targets for anti-allergy treatment, however the mechanism of receptor activation remain elusive. ...Histamine receptors play important roles in various pathophysiological conditions and are effective targets for anti-allergy treatment, however the mechanism of receptor activation remain elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human HR in complex with a G protein in an active conformation via a NanoBiT tethering strategy. The structure reveals that histamine activates receptor via interacting with the key residues of both transmembrane domain 3 (TM3) and TM6 to squash the binding pocket on the extracellular side and to open the cavity on the intracellular side for G engagement in a model of "squash to activate and expand to deactivate". The structure also reveals features for G coupling, including the interaction between intracellular loop 2 (ICL2) and the αN-β junction of G protein. The detailed analysis of our structure will provide a framework for understanding G-protein coupling selectivity and clues for designing novel antihistamines.
History
DepositionNov 9, 2020-
Header (metadata) releaseMar 31, 2021-
Map releaseMar 31, 2021-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7dfl
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30665.png

Downloads & links

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Map

FileDownload / File: emd_30665.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 256 pix.
= 276.48 Å		1.08 Å/pix.
x 256 pix.
= 276.48 Å		1.08 Å/pix.
x 256 pix.
= 276.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3 / Movie #1: 0.5
Minimum - Maximum-2.1475267 - 3.4589365
Average (Standard dev.)0.0014380204 (±0.07831866)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 276.48 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z276.480276.480276.480
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-2.1483.4590.001

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Supplemental data

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Sample components

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Entire : GPCR/G-protein complex

EntireName: GPCR/G-protein complex
Components
  • Complex: GPCR/G-protein complex
    • Protein or peptide: Histamine H1 receptor
    • 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
    • Protein or peptide: Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: scFv16
  • Ligand: HISTAMINE

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Supramolecule #1: GPCR/G-protein complex

SupramoleculeName: GPCR/G-protein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 130 kDa/nm

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Macromolecule #1: Histamine H1 receptor

MacromoleculeName: Histamine H1 receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.856035 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSLPNSSCLL EDKMCEGNKT TMASPQLMPL VVVLSTICLV TVGLNLLVLY AVRSERKLHT VGNLYIVSLS VADLIVGAVV MPMNILYLL MSKWSLGRPL CLFWLSMDYV ASTASIFSVF ILCIDRYRSV QQPLRYLKYR TKTRASATIL GAWFLSFLWV I PILGWNHF ...String:
MSLPNSSCLL EDKMCEGNKT TMASPQLMPL VVVLSTICLV TVGLNLLVLY AVRSERKLHT VGNLYIVSLS VADLIVGAVV MPMNILYLL MSKWSLGRPL CLFWLSMDYV ASTASIFSVF ILCIDRYRSV QQPLRYLKYR TKTRASATIL GAWFLSFLWV I PILGWNHF MQQTSVRRED KCETDFYDVT WFKVMTAIIN FYLPTLLMLW FYAKIYKAVR QHCQHRELIN RSLPSFSEIK LR PENPKGD AKKPGKESPW EVLKRKPKDA GGGSVLKSPS QTPKEMKSPV VFSQEDDREV DKLYCFPLDI VHMQAAAEGS SRD YVAVNR SHGQLKTDEQ GLNTHGASEI SEDQMLGDSQ SFSRTDSDTT TETAPGKGKL RSGSNTGLDY IKFTWKRLRS HSRQ YVSGL HMNRERKAAK QLGFIMAAFI LCWIPYFIFF MVIAFCKNCC NEHLHMFTIW LGYINSTLNP LIYPLCNENF KKTFK RILH IRS

UniProtKB: Histamine H1 receptor

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Macromolecule #2: 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: 2 / 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 #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.375332 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
NTASIAQARK LVEQLKMEAN IDRIKVSKAA ADLMAYCEAH AKEDPLLTPV PASENPFR

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

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Macromolecule #4: Guanine nucleotide-binding protein G(q) subunit alpha

MacromoleculeName: Guanine nucleotide-binding protein G(q) subunit alpha / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.090637 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: CTLSAEDKAA VERSKMIDRN LREDGEKARR ELKLLLLGTG ESGKSTFIKQ MRIIHGSGYS DEDKRGFTKL VYQNIFTAMQ AMIRAMDTL KIPYKHEHNK AHAQLVREVD VEKVSTFENP YVDAIRSLWS DPGIQECYDR RREYQLSDST KYYLNDLDRI A DSTYLPTQ ...String:
CTLSAEDKAA VERSKMIDRN LREDGEKARR ELKLLLLGTG ESGKSTFIKQ MRIIHGSGYS DEDKRGFTKL VYQNIFTAMQ AMIRAMDTL KIPYKHEHNK AHAQLVREVD VEKVSTFENP YVDAIRSLWS DPGIQECYDR RREYQLSDST KYYLNDLDRI A DSTYLPTQ QDVLRVRVPT TGIIEYPFDL QSVIFRMVDV GGQRSERRKW IHCFENVTSI MFLVALSEYD QVLVESDNEN RM EESKALF RTIITYPWFQ NSSVILFLNK KDLLEEKIMY SHLVDYFPEY DGPQRDAQAA REFILKMFVD LNPDSDKILY SHF TCATDT ENIRFVFAAV KDTILQLNLK EYNLV

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Macromolecule #5: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
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: HISTAMINE

MacromoleculeName: HISTAMINE / type: ligand / ID: 6 / Number of copies: 1 / Formula: HSM
Molecular weightTheoretical: 111.145 Da
Chemical component information

ChemComp-HSM:
HISTAMINE / neurotransmitter, hormone*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: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 56.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 0.01 mm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 169241
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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