3RZE

Structure of the human histamine H1 receptor in complex with doxepin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.217 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Structure of the human histamine H1 receptor complex with doxepin.

Shimamura, T.Shiroishi, M.Weyand, S.Tsujimoto, H.Winter, G.Katritch, V.Abagyan, R.Cherezov, V.Liu, W.Han, G.W.Kobayashi, T.Stevens, R.C.Iwata, S.

(2011) Nature 475: 65-70

  • DOI: https://doi.org/10.1038/nature10236
  • Primary Citation of Related Structures:  
    3RZE

  • PubMed Abstract: 

    The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp 428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys 191(5.39) and/or Lys 179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R.


  • Organizational Affiliation

    Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Kyoto 606-8501, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histamine H1 receptor, Lysozyme chimera452Homo sapiensTequatrovirus T4Mutation(s): 2 
Gene Names: HRH1E
EC: 3.2.1.17
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P35367 (Homo sapiens)
Explore P35367 
Go to UniProtKB:  P35367
PHAROS:  P35367
GTEx:  ENSG00000196639 
Find proteins for P00720 (Enterobacteria phage T4)
Explore P00720 
Go to UniProtKB:  P00720
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP00720P35367
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
OLC
Query on OLC

Download Ideal Coordinates CCD File 
G [auth A](2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate
C21 H40 O4
RZRNAYUHWVFMIP-GDCKJWNLSA-N
D7V
Query on D7V

Download Ideal Coordinates CCD File 
C [auth A](3Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
C19 H21 N O
ODQWQRRAPPTVAG-BOPFTXTBSA-N
5EH
Query on 5EH

Download Ideal Coordinates CCD File 
B [auth A](3E)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
C19 H21 N O
ODQWQRRAPPTVAG-GZTJUZNOSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.217 
  • Space Group: I 4 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.144α = 90
b = 88.144β = 90
c = 331.654γ = 90
Software Package:
Software NamePurpose
GDAdata collection
PHASERphasing
BUSTERrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2011-06-15
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-07-20
    Changes: Database references
  • Version 1.3: 2017-08-16
    Changes: Refinement description, Source and taxonomy
  • Version 1.4: 2018-01-24
    Changes: Structure summary
  • Version 1.5: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description