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- PDB-9jg1: Cryo-EM structure of Adriforant-bound Histamine receptor 4 H4R at... -

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Basic information

Entry
Database: PDB / ID: 9jg1
TitleCryo-EM structure of Adriforant-bound Histamine receptor 4 H4R at inactive state
Components
  • Histamine H4 receptor,Soluble cytochrome b562
  • anti-BRIL Fab Heavy chain
  • anti-BRIL Fab Light chain
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / Complex / 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)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.62 Å
AuthorsJin, S.S. / Zhang, H. / Jiang, Y.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 3, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Histamine H4 receptor,Soluble cytochrome b562
H: anti-BRIL Fab Heavy chain
L: anti-BRIL Fab Light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,5344
Polymers97,2723
Non-polymers2621
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Histamine H4 receptor,Soluble cytochrome b562 / H4R / HH4R / AXOR35 / G-protein coupled receptor 105 / GPRv53 / Pfi-013 / SP9144 / Cytochrome b-562


Mass: 48922.727 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: HRH4, GPCR105, cybC / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9H3N8, UniProt: P0ABE7
#2: Antibody anti-BRIL Fab Heavy chain


Mass: 24371.076 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#3: Antibody anti-BRIL Fab Light chain


Mass: 23977.793 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#4: Chemical ChemComp-A1EBW / Adriforant / 4-N-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine


Mass: 262.354 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H22N6 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of Histamine-bound Histamine receptor 3 H3R G protein complex
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.2
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 50 kV / Illumination mode: SPOT SCAN
Electron lensMode: DIFFRACTION / Nominal defocus max: 1800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.62 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 132359 / Symmetry type: POINT

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