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- PDB-9lrc: Cryo-EM structure of the histamine H4 receptor-Gi protein complex... -

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Entry
Database: PDB / ID: 9lrc
TitleCryo-EM structure of the histamine H4 receptor-Gi protein complex (Receptor focused)
ComponentsHistamine H4 receptor,Genome polyprotein
KeywordsMEMBRANE PROTEIN / GPCR / Class A GPCR / Histamine / Receptor
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 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / bioluminescence / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus ...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 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / bioluminescence / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / generation of precursor metabolites and energy / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / ribonucleoside triphosphate phosphatase activity / host cell cytoplasmic vesicle membrane / nucleoside-triphosphate phosphatase / channel activity / positive regulation of cytosolic calcium ion concentration / monoatomic ion transmembrane transport / G alpha (i) signalling events / chemical synaptic transmission / DNA replication / RNA helicase activity / endocytosis involved in viral entry into host cell / inflammatory response / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / dendrite / DNA-templated transcription / synapse / virion attachment to host cell / host cell nucleus / structural molecule activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane / plasma membrane
Similarity search - Function
Histamine H4 receptor / Green fluorescent protein, GFP / Picornavirus coat protein / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent 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 / Picornavirus coat protein / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent 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. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / 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
HISTAMINE / Genome polyprotein / Histamine H4 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.84 Å
AuthorsMatsuzaki, Y. / Sano, F.K. / Oshima, H.S. / Akasaka, H. / Kobayashi, K. / Tanaka, T. / Itoh, Y. / Shihoya, W. / Kise, Y. / Kusakizako, T. / Nureki, O.
Funding support Japan, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.1Jul 23, 2025Group: Data collection / Database references / Category: citation / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Histamine H4 receptor,Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,9082
Polymers77,7971
Non-polymers1111
Water181
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,Genome polyprotein / H4R / HH4R / AXOR35 / G-protein coupled receptor 105 / GPRv53 / Pfi-013 / SP9144


Mass: 77796.898 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRH4, GPCR105 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9H3N8, UniProt: B6F2F5, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#2: Chemical ChemComp-HSM / HISTAMINE


Mass: 111.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H9N3 / Feature type: SUBJECT OF INVESTIGATION / Comment: neurotransmitter, hormone*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
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: Histamine H4 receptor-Gi protein complex / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: This sample also includes Gi trimer and scFv16, which are not modeled because the density map is receptor-fucused.
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 8055

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4CTFFINDCTF correction
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.84 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 284264 / Symmetry type: POINT

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