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- EMDB-63325: Cryo-EM structure of the histamine H4 receptor-Gi protein complex... -

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Basic information

Entry
Database: EMDB / ID: EMD-63325
TitleCryo-EM structure of the histamine H4 receptor-Gi protein complex (Receptor focused)
Map data
Sample
  • Complex: Histamine H4 receptor-Gi protein complex
    • Protein or peptide: Histamine H4 receptor,Genome polyprotein
  • Ligand: HISTAMINE
  • Ligand: water
KeywordsGPCR / Class A GPCR / Histamine / Receptor / MEMBRANE PROTEIN
Function / homology
Function and homology information


Histamine receptors / histamine receptor activity / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / neurotransmitter receptor activity / regulation of MAPK cascade / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / bioluminescence / generation of precursor metabolites and energy / picornain 2A ...Histamine receptors / histamine receptor activity / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / neurotransmitter receptor activity / regulation of MAPK cascade / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / bioluminescence / generation of precursor metabolites and energy / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / nucleoside-triphosphate phosphatase / positive regulation of cytosolic calcium ion concentration / channel activity / monoatomic ion transmembrane transport / G alpha (i) signalling events / chemical synaptic transmission / DNA replication / RNA helicase activity / inflammatory response / endocytosis involved in viral entry into host cell / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / synapse / dendrite / virion attachment to host cell / host cell nucleus / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane / plasma membrane
Similarity search - Function
Histamine H4 receptor / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Picornavirus coat protein / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain ...Histamine H4 receptor / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Picornavirus coat protein / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Picornavirus capsid / picornavirus capsid protein / Helicase, superfamily 3, single-stranded RNA virus / Superfamily 3 helicase of positive ssRNA viruses domain profile. / Helicase, superfamily 3, single-stranded DNA/RNA virus / RNA helicase / Picornavirus/Calicivirus coat protein / Viral coat protein 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) / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Histamine H4 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.84 Å
AuthorsMatsuzaki Y / Sano FK / Oshima HS / Akasaka H / Kobayashi K / Tanaka T / Itoh Y / Shihoya W / Kise Y / Kusakizako T / Nureki O
Funding support Japan, 1 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS) Japan
CitationJournal: Commun Biol / Year: 2025
Title: Structural insights into ligand recognition and G protein preferences across histamine receptors.
Authors: Yuma Matsuzaki / Fumiya K Sano / Hidetaka S Oshima / Hiroaki Akasaka / Kazuhiro Kobayashi / Tatsuki Tanaka / Yuzuru Itoh / Wataru Shihoya / Yoshiaki Kise / Tsukasa Kusakizako / Asuka Inoue / Osamu Nureki /
Abstract: Histamine exerts critical physiological roles by activating four receptor subtypes, each exhibiting a specific G protein preference. Among these, the histamine H receptor (HR) modulates chemotaxis ...Histamine exerts critical physiological roles by activating four receptor subtypes, each exhibiting a specific G protein preference. Among these, the histamine H receptor (HR) modulates chemotaxis and interferon production through G protein activation, suggesting its therapeutic potential. Despite its physiological significance, the mechanisms underlying HR signalling and G protein preference across histamine receptors remain poorly understood. Here, we present the cryo-electron microscopy structure of the HR-G complex, revealing unique mechanisms of histamine recognition and receptor activation. We further solved the structures of the histamine H receptor (HR) bound to the non-canonical G proteins G and G. Through a combination of functional and computational analyses, we identified the intracellular loop 2 as a critical determinant of G protein preference in HR and HR. Collectively, our comprehensive study revealed the structural basis for distinct mechanisms of ligand recognition and receptor activation, offering a profound insight into G protein preference across receptor subtypes.
History
DepositionJan 30, 2025-
Header (metadata) releaseJun 11, 2025-
Map releaseJun 11, 2025-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_63325.png

Downloads & links

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Map

FileDownload / File: emd_63325.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.97 Å/pix.
x 240 pix.
= 232.4 Å		0.97 Å/pix.
x 240 pix.
= 232.4 Å		0.97 Å/pix.
x 240 pix.
= 232.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.96833 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.85
Minimum - Maximum-4.5110674 - 6.582135
Average (Standard dev.)0.001764393 (±0.081456974)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 232.39992 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_63325_msk_1.map
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Half map: #1

Fileemd_63325_half_map_1.map
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Half map: #2

Fileemd_63325_half_map_2.map
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Sample components

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Entire : Histamine H4 receptor-Gi protein complex

EntireName: Histamine H4 receptor-Gi protein complex
Components
  • Complex: Histamine H4 receptor-Gi protein complex
    • Protein or peptide: Histamine H4 receptor,Genome polyprotein
  • Ligand: HISTAMINE
  • Ligand: water

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Supramolecule #1: Histamine H4 receptor-Gi protein complex

SupramoleculeName: Histamine H4 receptor-Gi protein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Histamine H4 receptor,Genome polyprotein

MacromoleculeName: Histamine H4 receptor,Genome polyprotein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 77.796898 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKGSGGSS GGGSPDTNST INLSLSTRVT LAFFMSLVAF AIMLGNALVI LAFVVDKNLR HRSSYFFLN LAISDFFVGV ISIPLYIPHT LFEWDFGKEI CVFWLTTDYL LCTASVYNIV LISYDRYLSV SNAVSYRTQH T GVLKIVTL ...String:
MKTIIALSYI FCLVFADYKD DDDKGSGGSS GGGSPDTNST INLSLSTRVT LAFFMSLVAF AIMLGNALVI LAFVVDKNLR HRSSYFFLN LAISDFFVGV ISIPLYIPHT LFEWDFGKEI CVFWLTTDYL LCTASVYNIV LISYDRYLSV SNAVSYRTQH T GVLKIVTL MVAVWVLAFL VNGPMILVSE SWKDEGSECE PGFFSEWYIL AITSFLEFVI PVILVAYFNM NIYWSLWKRD HL SRCQSHP GLTAVSSNIC GHSFRGRLSS RRSLSASTEV PASFHSERQR RKSSLMFSSR TKMNSNTIAS KMGSFSQSDS VAL HQREHV ELLRARRLAK SLAILLGVFA VCWAPYSLFT IVLSFYSSAT GPKSVWYRIA FWLQWFNSFV NPLLYPLCHK RFQK AFLKI FCIKKQPLPS QHSRSVSSGG SGGGSGGSSG GGSLEVLFQG PVSKGEELFT GVVPILVELD GDVNGHKFSV SGEGE GDAT YGKLTLKFIC TTGKLPVPWP TLVTTLTYGV QCFSRYPDHM KQHDFFKSAM PEGYVQERTI FFKDDGNYKT RAEVKF EGD TLVNRIELKG IDFKEDGNIL GHKLEYNYNS HNVYIMADKQ KNGIKVNFKI RHNIEDGSVQ LADHYQQNTP IGDGPVL LP DNHYLSTQSK LSKDPNEKRD HMVLLEFVTA AGITLGMDEL YKHHHHHHHH

UniProtKB: Histamine H4 receptor, Genome polyprotein

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Macromolecule #2: HISTAMINE

MacromoleculeName: HISTAMINE / type: ligand / ID: 2 / Number of copies: 1 / Formula: HSM
Molecular weightTheoretical: 111.145 Da
Chemical component information

ChemComp-HSM:
HISTAMINE / neurotransmitter, hormone*YM

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Macromolecule #3: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 1 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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 / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample also includes Gi trimer and scFv16, which are not modeled because the density map is receptor-fucused.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 8055 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7yfd

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.84 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 284264
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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