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- PDB-7yfd: Cryo-EM structure of the imetit-bound histamine H4 receptor and G... -

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Basic information

Entry
Database: PDB / ID: 7yfd
TitleCryo-EM structure of the imetit-bound histamine H4 receptor and Gq complex
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Engineered G-alpha-q
  • Histamine H4 receptor
  • Nb35
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR / Aminergic receptor / Histamine receptor
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 / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors ...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 / 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 / positive regulation of cytosolic calcium ion concentration / 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 H4 receptor / 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 ...Histamine H4 receptor / 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
CHOLESTEROL / 2-(1~{H}-imidazol-5-yl)ethyl carbamimidothioate / 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 / Histamine H4 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsIm, D. / Iwata, S. / Asada, H.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)JP21am0101079 Japan
CitationJournal: Nat Commun / Year: 2023
Title: Structural insights into the agonists binding and receptor selectivity of human histamine H receptor.
Authors: Dohyun Im / Jun-Ichi Kishikawa / Yuki Shiimura / Hiromi Hisano / Akane Ito / Yoko Fujita-Fujiharu / Yukihiko Sugita / Takeshi Noda / Takayuki Kato / Hidetsugu Asada / So Iwata /
Abstract: Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H receptor (HR) is a potential therapeutic target for chronic ...Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H receptor (HR) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the HR-G complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe344, which, in turn, form the "aromatic slot". The results provide insights into the molecular underpinnings of the agonism of HR and subtype selectivity of histamine receptors, and show that the HR structures may be valuable in rational drug design of drugs targeting the HR.
History
DepositionJul 8, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 25, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2023Group: Data collection / Database references / Structure summary
Category: audit_author / citation ...audit_author / citation / citation_author / em_author_list / struct_keywords
Item: _audit_author.name / _citation.journal_volume ..._audit_author.name / _citation.journal_volume / _citation.page_first / _citation.pdbx_database_id_DOI / _em_author_list.author / _struct_keywords.text
Revision 1.2Nov 22, 2023Group: Database references / Category: citation / Item: _citation.title
Revision 1.3May 8, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.4Oct 16, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Engineered G-alpha-q
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: scFv16
R: Histamine H4 receptor
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nb35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,7509
Polymers195,8076
Non-polymers9443
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AR

#1: Protein Engineered G-alpha-q


Mass: 41724.383 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#4: Protein Histamine H4 receptor / H4R / HH4R / AXOR35 / G-protein coupled receptor 105 / GPRv53 / Pfi-013 / SP9144


Mass: 62137.711 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRH4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9H3N8

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 42282.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody , 2 types, 2 molecules CN

#3: Antibody scFv16


Mass: 27784.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Antibody Nb35


Mass: 14016.636 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Spodoptera frugiperda (fall armyworm)

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Non-polymers , 2 types, 3 molecules

#7: Chemical ChemComp-ITF / 2-(1~{H}-imidazol-5-yl)ethyl carbamimidothioate


Mass: 170.235 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H10N4S / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O

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Details

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

Component
IDNameTypeEntity IDParent-IDSource
1Imetit bound histamine h4 receptor in complex with GqCOMPLEX#1-#60RECOMBINANT
2Engineered G-alpha-qCOMPLEX#11RECOMBINANT
3Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#21RECOMBINANT
4scFv16COMPLEX#31RECOMBINANT
5Histamine H4 receptorCOMPLEX#41RECOMBINANT
6Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#51RECOMBINANT
7Nb35COMPLEX#61RECOMBINANT
Molecular weightValue: 0.19 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Mus musculus (house mouse)10090
54Homo sapiens (human)9606
65Homo sapiens (human)9606
76Lama glama (llama)9844
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Spodoptera frugiperda (fall armyworm)7108
32Spodoptera frugiperda (fall armyworm)7108
43Spodoptera frugiperda (fall armyworm)7108
54Spodoptera frugiperda (fall armyworm)7108
65Spodoptera frugiperda (fall armyworm)7108
76Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
2SerialEMimage acquisition
4cryoSPARCCTF correction
CTF correctionType: NONE
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 628467 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00310159
ELECTRON MICROSCOPYf_angle_d0.52713783
ELECTRON MICROSCOPYf_dihedral_angle_d5.7331423
ELECTRON MICROSCOPYf_chiral_restr0.0431548
ELECTRON MICROSCOPYf_plane_restr0.0051736

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