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- EMDB-61447: Cryo-EM structure of Adriforant-bound Histamine receptor 4 H4R at... -

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Basic information

Entry
Database: EMDB / ID: EMD-61447
TitleCryo-EM structure of Adriforant-bound Histamine receptor 4 H4R at inactive state
Map data
Sample
  • Complex: Cryo-EM structure of Histamine-bound Histamine receptor 3 H3R G protein complex
    • Protein or peptide: Histamine H4 receptor,Soluble cytochrome b562
    • Protein or peptide: anti-BRIL Fab Heavy chain
    • Protein or peptide: anti-BRIL Fab Light chain
  • Ligand: Adriforant
KeywordsComplex / MEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


Histamine receptors / histamine receptor activity / neurotransmitter receptor activity / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / regulation of MAPK cascade / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / electron transport chain / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / chemical synaptic transmission ...Histamine receptors / histamine receptor activity / neurotransmitter receptor activity / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / regulation of MAPK cascade / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / electron transport chain / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / chemical synaptic transmission / periplasmic space / electron transfer activity / iron ion binding / inflammatory response / heme binding / synapse / dendrite / plasma membrane
Similarity search - Function
Histamine H4 receptor / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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)
Similarity search - Domain/homology
Soluble cytochrome b562 / Histamine H4 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.62 Å
AuthorsJin SS / Zhang H / Jiang Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Acta Pharmacol Sin / Year: 2025
Title: Decoding ligand recognition and constitutive activation of histamine H3 and H4 receptors.
Authors: San-Shan Jin / Heng Zhang / Jia-Hui Yan / Can-Rong Wu / Xiao-Qing Cai / Kai Wu / Ming-Wei Wang / H Eric Xu / De-Hua Yang / Yi Jiang /
Abstract: Histamine H3 receptor (H3R) and H4 receptor (H4R) are key members of the histamine receptor family, with H3R as a potential target for narcolepsy treatments and H4R as a candidate for next-generation ...Histamine H3 receptor (H3R) and H4 receptor (H4R) are key members of the histamine receptor family, with H3R as a potential target for narcolepsy treatments and H4R as a candidate for next-generation antihistamines for inflammatory and allergic diseases. Although progress has been made in understanding the structure of histamine receptors, the detailed mechanisms of ligand recognition and receptor antagonism for H3R and H4R remain unclear. In this study, using cryo-electron microscopy, we present an inactive structure of H4R bound to a selective antagonist, adriforant, and two Gi-coupled structures of H3R and H4R in complex with histamine. Our structural and mutagenesis analyses provide insights into the selective binding of adriforant to H4R and the recognition of histamine across histamine receptors. Our findings also uncovered distinct antagonistic mechanisms for H3R and H4R and identified the role of aromatic amino acids on extracellular loop 2 in modulating the constitutive activity of H3R and H4R. These findings advance our knowledge of the functional modulation of histamine receptors, providing a foundation for the development of targeted therapeutics for neurological and immune-related disorders.
History
DepositionSep 5, 2024-
Header (metadata) releaseDec 3, 2025-
Map releaseDec 3, 2025-
UpdateDec 3, 2025-
Current statusDec 3, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61447.png

Downloads & links

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Map

FileDownload / File: emd_61447.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 320 pix.
= 233.6 Å		0.73 Å/pix.
x 320 pix.
= 233.6 Å		0.73 Å/pix.
x 320 pix.
= 233.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.19
Minimum - Maximum-0.97170746 - 1.4590881
Average (Standard dev.)-0.00037709065 (±0.033163182)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 233.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_61447_additional_1.map
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Half map: #2

Fileemd_61447_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_61447_half_map_2.map
Projections & Slices
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Sample components

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Entire : Cryo-EM structure of Histamine-bound Histamine receptor 3 H3R G p...

EntireName: Cryo-EM structure of Histamine-bound Histamine receptor 3 H3R G protein complex
Components
  • Complex: Cryo-EM structure of Histamine-bound Histamine receptor 3 H3R G protein complex
    • Protein or peptide: Histamine H4 receptor,Soluble cytochrome b562
    • Protein or peptide: anti-BRIL Fab Heavy chain
    • Protein or peptide: anti-BRIL Fab Light chain
  • Ligand: Adriforant

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Supramolecule #1: Cryo-EM structure of Histamine-bound Histamine receptor 3 H3R G p...

SupramoleculeName: Cryo-EM structure of Histamine-bound Histamine receptor 3 H3R G protein complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Histamine H4 receptor,Soluble cytochrome b562

MacromoleculeName: Histamine H4 receptor,Soluble cytochrome b562 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 48.922727 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MPDTNSTINL SLSTRVTLAF FMSLVAFAIM LGNALVILAF VVDKNLRHRS SYFFLNLAIS DFFVGVISIP LYIPHTLFEW DFGKEICVF WLTTDYLLCT ASVYNIVLIS YDRYLSVSNA VSYRTQHTGV LKIVTLMVAV WVLAFLVNGP MILVSESWKD E GSECEPGF ...String:
MPDTNSTINL SLSTRVTLAF FMSLVAFAIM LGNALVILAF VVDKNLRHRS SYFFLNLAIS DFFVGVISIP LYIPHTLFEW DFGKEICVF WLTTDYLLCT ASVYNIVLIS YDRYLSVSNA VSYRTQHTGV LKIVTLMVAV WVLAFLVNGP MILVSESWKD E GSECEPGF FSEWYILAIT SFLEFVIPVI LVAYFNMNIY WSLWKRDHLA RRQLADLEDN WETLNDNLKV IEKADNAAQV KD ALTKMRA AALDAQKATP PKLEDKSPDS PEMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LER ARSTLQ REHVELLRAR RLAKSLAILL GVFAVCWAPY SLFTIVLSFY SSATGPKSVW YRIAFWLQWF NSFVNPLLYP LCHK RFQKA FLKIFCIKKQ PLPSQHSRSV SS

UniProtKB: Histamine H4 receptor, Soluble cytochrome b562, Histamine H4 receptor

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Macromolecule #2: anti-BRIL Fab Heavy chain

MacromoleculeName: anti-BRIL Fab Heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.371076 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MSDIQMTQSP SSLSASVGDR VTITCRASQS VSSAVAWYQQ KPGKAPKLLI YSASSLYSGV PSRFSGSRSG TDFTLTISSL QPEDFATYY CQQYLYYSLV TFGQGTKVEI KRTVAAPSVF IFPPSDSQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE ...String:
MSDIQMTQSP SSLSASVGDR VTITCRASQS VSSAVAWYQQ KPGKAPKLLI YSASSLYSGV PSRFSGSRSG TDFTLTISSL QPEDFATYY CQQYLYYSLV TFGQGTKVEI KRTVAAPSVF IFPPSDSQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGGHH HHHH

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Macromolecule #3: anti-BRIL Fab Light chain

MacromoleculeName: anti-BRIL Fab Light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.977793 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MSEVQLVESG GGLVQPGGSL RLSCAASGFN VVVFSIHWVR QAPGKGLEWV AYISSSSGST SYADSVKGRF TISADTSKNT AYLQMNSLR AEDTAVYYCA RWGYWPGEPW WKAFDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF P EPVTVSWN ...String:
MSEVQLVESG GGLVQPGGSL RLSCAASGFN VVVFSIHWVR QAPGKGLEWV AYISSSSGST SYADSVKGRF TISADTSKNT AYLQMNSLR AEDTAVYYCA RWGYWPGEPW WKAFDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF P EPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKKVEP

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Macromolecule #4: Adriforant

MacromoleculeName: Adriforant / type: ligand / ID: 4 / Number of copies: 1 / Formula: A1EBW
Molecular weightTheoretical: 262.354 Da

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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: 7.2
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TECNAI ARCTICA
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 50 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: DIFFRACTION / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.62 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 132359
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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