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- EMDB-38075: CryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab ... -

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Basic information

Entry
Database: EMDB / ID: EMD-38075
TitleCryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab complex with astemizole
Map data
Sample
  • Complex: CryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab complex with astemizole
    • Protein or peptide: Histamine H1 receptor,Soluble cytochrome b562
  • Ligand: 1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-amine
KeywordsGPCR / MEMBRANE PROTEIN
Function / homology
Function and homology information


Histamine receptors / histamine receptor activity / cellular response to histamine / regulation of vascular permeability / 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 / electron transport chain / visual learning ...Histamine receptors / histamine receptor activity / cellular response to histamine / regulation of vascular permeability / 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 / electron transport chain / visual learning / regulation of synaptic plasticity / memory / phospholipase C-activating G protein-coupled receptor signaling pathway / chemical synaptic transmission / G alpha (q) signalling events / periplasmic space / electron transfer activity / inflammatory response / iron ion binding / G protein-coupled receptor signaling pathway / dendrite / heme binding / synapse / 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
Soluble cytochrome b562 / Histamine H1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsWang DD / Guo Q / Tao YY
Funding support China, 1 items
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, 2023-
Header (metadata) releaseJan 17, 2024-
Map releaseJan 17, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38075.png

Downloads & links

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Map

FileDownload / File: emd_38075.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 336 pix.
= 356.16 Å		1.06 Å/pix.
x 336 pix.
= 356.16 Å		1.06 Å/pix.
x 336 pix.
= 356.16 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.443
Minimum - Maximum-6.266976 - 8.873631
Average (Standard dev.)0.000037036887 (±0.049496047)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 356.15997 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38075_half_map_1.map
Projections & Slices
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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_38075_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : CryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab ...

EntireName: CryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab complex with astemizole
Components
  • Complex: CryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab complex with astemizole
    • Protein or peptide: Histamine H1 receptor,Soluble cytochrome b562
  • Ligand: 1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-amine

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Supramolecule #1: CryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab ...

SupramoleculeName: CryoEM structure of the histamine H1 receptor-BRIL/Anti BRIL Fab complex with astemizole
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Histamine H1 receptor,Soluble cytochrome b562

MacromoleculeName: Histamine H1 receptor,Soluble cytochrome b562 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.629363 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDKTT MASPQLMPLV VVLSTICLVT VGLNLLVLYA VRSERKLHTV GNLYIVSLSV ADLIVGAVVM PMNILYLLMS KWSLGRPLC LFWLSMDYVA STASIFSVFI LCIDRYRSVQ QPLRYLKYRT KTRASATILG AWFLSFLWVI PILGWNHFMQ Q TSVRREDK ...String:
DYKDDDDKTT MASPQLMPLV VVLSTICLVT VGLNLLVLYA VRSERKLHTV GNLYIVSLSV ADLIVGAVVM PMNILYLLMS KWSLGRPLC LFWLSMDYVA STASIFSVFI LCIDRYRSVQ QPLRYLKYRT KTRASATILG AWFLSFLWVI PILGWNHFMQ Q TSVRREDK CETDFYDVTW FKVMTAIINF YLPTLLMLWF YAKIYKAVKR QLADLEDNWE TLNDNLKVIE KADNAAQVKD AL TKMRAAA LDAQKASGSG SPEMKDFRHG FDILVGQIDD ALKLANEGKV KEAQAAAEQL KTTRNAYIQK YLKFCNRERK AAK QLGFIM AAFILCWIPY FIFFMVIAFC KNCCNEHLHM FTIWLGYINS TLNPLIYPLC NENFKKTFKR ILKIAALKEK IAAL KEKIA ALKEAEEKRA SRLEEELRRR LTEGSHHHHH HHH

UniProtKB: Histamine H1 receptor, Soluble cytochrome b562

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Macromolecule #2: 1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperid...

MacromoleculeName: 1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-amine
type: ligand / ID: 2 / Number of copies: 1 / Formula: XB7
Molecular weightTheoretical: 458.57 Da
Chemical component information

ChemComp-XB7:
1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-amine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: NITROGEN

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 357476
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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