2AOT

Histamine Methyltransferase Complexed with the Antihistamine Drug Diphenhydramine

Summary for 2AOT

• Entry DOI: 10.2210/pdb2aot/pdb
• Related: 1JQD 1JQE 2AOU 2AOV 2AOW 2AOX
• Descriptor: Histamine N-methyltransferase, N-[2-(BENZHYDRYLOXY)ETHYL]-N,N-DIMETHYLAMINE, S-ADENOSYL-L-HOMOCYSTEINE, ... (5 entities in total)
• Functional Keywords: classic methyltransferase fold, protein-drug complex, transferase
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P50135 P50135
• Total number of polymer chains: 2
• Total formula weight: 68009.57

Authors

Horton, J.R.,Sawada, K.,Nishibori, M.,Cheng, X. (deposition date: 2005-08-14, release date: 2005-09-13, Last modification date: 2024-10-09)

Primary citation

Horton, J.R.,Sawada, K.,Nishibori, M.,Cheng, X.
Structural basis for inhibition of histamine N-methyltransferase by diverse drugs
J.Mol.Biol., 353:334-344, 2005

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.

PubMed: 16168438
DOI: 10.1016/j.jmb.2005.08.040

Experimental method

X-RAY DIFFRACTION (1.9 Å)