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- PDB-8yn8: Cryo-EM structure of histamine H3 receptor in complex with proxyf... -

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Basic information

Entry
Database: PDB / ID: 8yn8
TitleCryo-EM structure of histamine H3 receptor in complex with proxyfan and miniGo
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Antibody fragment scFv16
  • Engineered guanine nucleotide-binding protein G(o) subunit alpha,Guanine nucleotide-binding protein G(o) subunit alpha
  • Histamine H3 receptor
KeywordsSIGNALING PROTEIN / GPCR
Function / homology
Function and homology information


Histamine receptors / histamine receptor activity / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / neurotransmitter receptor activity / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / neurotransmitter secretion / vesicle docking involved in exocytosis / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction ...Histamine receptors / histamine receptor activity / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / neurotransmitter receptor activity / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / neurotransmitter secretion / vesicle docking involved in exocytosis / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / parallel fiber to Purkinje cell synapse / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / postsynaptic modulation of chemical synaptic transmission / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / muscle contraction / locomotory behavior / negative regulation of insulin secretion / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / 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 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / 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 / presynapse / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity / presynaptic membrane / cell body / GTPase binding / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / chemical synaptic transmission / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / postsynaptic membrane / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / dendrite / synapse / GTP binding / protein-containing complex binding / glutamatergic synapse / signal transduction / extracellular exosome / metal ion binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Histamine H3 receptor / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain ...Histamine H3 receptor / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / G protein beta WD-40 repeat protein / 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. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / CHOLESTEROL / Guanine nucleotide-binding protein G(o) subunit alpha / 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 H3 receptor
Similarity search - Component
Biological speciessynthetic construct (others)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.77 Å
AuthorsZhang, X. / Liu, G. / Li, X. / Gong, W.
Funding support China, 2items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2019YFA0904100 China
National Natural Science Foundation of China (NSFC)T2221005 China
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis of ligand recognition and activation of the histamine receptor family.
Authors: Xuan Zhang / Guibing Liu / Ya-Ni Zhong / Ru Zhang / Chuan-Cheng Yang / Canyang Niu / Xuanyu Pu / Jingjing Sun / Tianyao Zhang / Lejin Yang / Chao Zhang / Xiu Li / Xinyuan Shen / Peng Xiao / ...Authors: Xuan Zhang / Guibing Liu / Ya-Ni Zhong / Ru Zhang / Chuan-Cheng Yang / Canyang Niu / Xuanyu Pu / Jingjing Sun / Tianyao Zhang / Lejin Yang / Chao Zhang / Xiu Li / Xinyuan Shen / Peng Xiao / Jin-Peng Sun / Weimin Gong /
Abstract: Histamine is a biogenic amine that is critical in various physiological and pathophysiological processes, including but not limited to allergic reactions, wakefulness, gastric acid secretion and ...Histamine is a biogenic amine that is critical in various physiological and pathophysiological processes, including but not limited to allergic reactions, wakefulness, gastric acid secretion and neurotransmission. Here, we determine 9 cryo-electron microscopy (cryo-EM) structures of the 4 histamine receptors in complex with four different G protein subtypes, with endogenous or synthetic agonists bound. Inside the ligand pocket, we identify key motifs for the recognition of histamine, the distinct binding orientations of histamine and three subpockets that facilitate the design of specific ligands. In addition, we also identify key residues responsible for the selectivity of immethridine. Moreover, we reveal distinct structural features as determinants of Gq vs. Gs or Gs vs. Gi coupling differences among the histamine receptors. Our study provides a structural framework for understanding the ligand recognition and G protein coupling of all 4 histamine receptors, which may facilitate the rational design of ligands targeting these receptors.
History
DepositionMar 10, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.page_last / _citation.pdbx_database_id_PubMed ..._citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.2Nov 13, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.3Nov 27, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Engineered guanine nucleotide-binding protein G(o) subunit alpha,Guanine nucleotide-binding protein G(o) subunit alpha
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: Antibody fragment scFv16
R: Histamine H3 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)176,08611
Polymers173,9375
Non-polymers2,1506
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

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Protein , 2 types, 2 molecules AR

#1: Protein Engineered guanine nucleotide-binding protein G(o) subunit alpha,Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 25286.922 Da / Num. of mol.: 1 / Mutation: A227D,G230D,I332A,V335I
Source method: isolated from a genetically manipulated source
Details: Residues 232-241 of the wild-type protein were truncated in this engineered protein.
Source: (gene. exp.) synthetic construct (others), (gene. exp.) Homo sapiens (human)
Gene: GNAO1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P09471
#5: Protein Histamine H3 receptor / H3R / HH3R / G-protein coupled receptor 97


Mass: 72568.703 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRH3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9Y5N1

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

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


Mass: 40845.559 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
#3: 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 , 1 types, 1 molecules E

#4: Antibody Antibody fragment scFv16


Mass: 27374.430 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Trichoplusia ni (cabbage looper)

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Non-polymers , 2 types, 6 molecules

#6: Chemical ChemComp-A1LY3 / 5-(3-phenylmethoxypropyl)-1H-imidazole


Mass: 216.279 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H16N2O / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 5 / 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

ComponentName: Proxyfan-H3R-miniGo-scFv16 complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
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: 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: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85007 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029136
ELECTRON MICROSCOPYf_angle_d0.40112429
ELECTRON MICROSCOPYf_dihedral_angle_d9.0953182
ELECTRON MICROSCOPYf_chiral_restr0.0381426
ELECTRON MICROSCOPYf_plane_restr0.0031545

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