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- PDB-8x5y: CryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab ... -

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Basic information

Entry
Database: PDB / ID: 8x5y
TitleCryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab complex with astemizole
ComponentsHistamine H1 receptor,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / GPCR
Function / homology
Function and homology information


Histamine receptors / histamine receptor activity / regulation of vascular permeability / cellular response to histamine / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of vasoconstriction / regulation of synaptic plasticity / visual learning ...Histamine receptors / histamine receptor activity / regulation of vascular permeability / cellular response to histamine / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of vasoconstriction / regulation of synaptic plasticity / visual learning / memory / phospholipase C-activating G protein-coupled receptor signaling pathway / chemical synaptic transmission / G alpha (q) signalling events / electron transfer activity / periplasmic space / inflammatory response / iron ion binding / G protein-coupled receptor signaling pathway / dendrite / synapse / heme binding / plasma membrane / cytosol
Similarity search - Function
Histamine H1 receptor / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / 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
Chem-XB7 / Soluble cytochrome b562 / Histamine H1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsWang, D.D. / Guo, Q. / Tao, Y.Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2024
Title: Molecular mechanism of antihistamines recognition and regulation of the histamine H receptor.
Authors: Dandan Wang / Qiong Guo / Zhangsong Wu / Ming Li / Binbin He / Yang Du / Kaiming Zhang / Yuyong Tao /
Abstract: Histamine receptors are a group of G protein-coupled receptors (GPCRs) that play important roles in various physiological and pathophysiological conditions. Antihistamines that target the histamine H ...Histamine receptors are a group of G protein-coupled receptors (GPCRs) that play important roles in various physiological and pathophysiological conditions. Antihistamines that target the histamine H receptor (HR) have been widely used to relieve the symptoms of allergy and inflammation. Here, to uncover the details of the regulation of HR by the known second-generation antihistamines, thereby providing clues for the rational design of newer antihistamines, we determine the cryo-EM structure of HR in the apo form and bound to different antihistamines. In addition to the deep hydrophobic cavity, we identify a secondary ligand-binding site in HR, which potentially may support the introduction of new derivative groups to generate newer antihistamines. Furthermore, these structures show that antihistamines exert inverse regulation by utilizing a shared phenyl group that inserts into the deep cavity and block the movement of the toggle switch residue W428. Together, these results enrich our understanding of GPCR modulation and facilitate the structure-based design of novel antihistamines.
History
DepositionNov 20, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 17, 2024Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
B: Histamine H1 receptor,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,0882
Polymers50,6291
Non-polymers4591
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Histamine H1 receptor,Soluble cytochrome b562 / H1R / HH1R / Cytochrome b-562


Mass: 50629.363 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: HRH1, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35367, UniProt: P0ABE7
#2: Chemical ChemComp-XB7 / 1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-amine / Astemizole


Mass: 458.570 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H31FN4O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: CryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab complex with astemizole
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Escherichia coli (E. coli)562
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: NITROGEN

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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 FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 357476 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0042360
ELECTRON MICROSCOPYf_angle_d0.7293205
ELECTRON MICROSCOPYf_dihedral_angle_d6.54311
ELECTRON MICROSCOPYf_chiral_restr0.044364
ELECTRON MICROSCOPYf_plane_restr0.006377

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