2AOU

Histamine Methyltransferase Complexed with the Antimalarial Drug Amodiaquine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.213 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structural basis for inhibition of histamine N-methyltransferase by diverse drugs

Horton, J.R.Sawada, K.Nishibori, M.Cheng, X.

(2005) J Mol Biol 353: 334-344

  • DOI: https://doi.org/10.1016/j.jmb.2005.08.040
  • Primary Citation of Related Structures:  
    2AOT, 2AOU, 2AOV, 2AOW, 2AOX

  • PubMed Abstract: 

    In mammals, histamine action is terminated through metabolic inactivation by histamine N-methyltransferase (HNMT) and diamine oxidase. In addition to three well-studied pharmacological functions, smooth muscle contraction, increased vascular permeability, and stimulation of gastric acid secretion, histamine plays important roles in neurotransmission, immunomodulation, and regulation of cell proliferation. The histamine receptor H1 antagonist diphenhydramine, the antimalarial drug amodiaquine, the antifolate drug metoprine, and the anticholinesterase drug tacrine (an early drug for Alzheimer's disease) are surprisingly all potent HNMT inhibitors, having inhibition constants in the range of 10-100nM. We have determined the structural mode of interaction of these four inhibitors with HNMT. Despite their structural diversity, they all occupy the histamine-binding site, thus blocking access to the enzyme's active site. Near the N terminus of HNMT, several aromatic residues (Phe9, Tyr15, and Phe19) adopt different rotamer conformations or become disordered in the enzyme-inhibitor complexes, accommodating the diverse, rigid hydrophobic groups of the inhibitors. The maximized shape complementarity between the protein aromatic side-chains and aromatic ring(s) of the inhibitors are responsible for the tight binding of these varied inhibitors.


  • Organizational Affiliation

    Department of Biochemistry Emory University School of Medicine, 1510 Clifton Road Atlanta, GA 30322, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histamine N-methyltransferase292Homo sapiensMutation(s): 3 
Gene Names: HNMT
EC: 2.1.1.8
UniProt & NIH Common Fund Data Resources
Find proteins for P50135 (Homo sapiens)
Explore P50135 
Go to UniProtKB:  P50135
PHAROS:  P50135
GTEx:  ENSG00000150540 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP50135
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Histamine N-methyltransferase292Homo sapiensMutation(s): 3 
Gene Names: HNMT
UniProt & NIH Common Fund Data Resources
Find proteins for P50135 (Homo sapiens)
Explore P50135 
Go to UniProtKB:  P50135
PHAROS:  P50135
GTEx:  ENSG00000150540 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP50135
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CQA
Query on CQA

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth B],
F [auth B]
4-[(7-CHLOROQUINOLIN-4-YL)AMINO]-2-[(DIETHYLAMINO)METHYL]PHENOL
C20 H22 Cl N3 O
OVCDSSHSILBFBN-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CSO
Query on CSO
A
L-PEPTIDE LINKINGC3 H7 N O3 SCYS
Binding Affinity Annotations 
IDSourceBinding Affinity
CQA Binding MOAD:  2AOU Ki: 18.6 (nM) from 1 assay(s)
BindingDB:  2AOU Ki: 19 (nM) from 1 assay(s)
PDBBind:  2AOU Ki: 18.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.213 
  • Space Group: P 6
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 130.89α = 90
b = 130.89β = 90
c = 63.32γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
GLRFphasing
CNSrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-09-13
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary
  • Version 1.4: 2023-11-15
    Changes: Data collection