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. 2005 Oct 21;353(2):334-344.
doi: 10.1016/j.jmb.2005.08.040.

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

John R Horton #  1 , Ken Sawada #  1 , Masahiro Nishibori  2 , Xiaodong Cheng  1
Affiliations

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

John R Horton et al. J Mol Biol. .

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.

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Figures

Figure 1
Figure 1
Interactions of HNMT and diphenhydramine. (a) Chemical structure of diphenhydramine (top panel). The simulated-annealing omit electron density map is contoured at 3.5σ above the mean (bottom panel). (b) Ribbon diagram of HNMT-diphenhydramine-AdoHcy. The N terminus is in blue and the C terminus in red. (c) Active site pocket of HNMT reconstituted from the four structures. Residues adopting different rotomer conformation or disordered are labeled in white letter against red background. The side-chains of Glu246 and Tyr15 are disordered in the complex with diphenhydramine; the side-chain of Phe9 is disordered in the complexes with amodiaquine and metoprine, and adopts one rotamer in diphenhydramine and a different one in tacrine. (d) Detailed plot of HNMT–diphenhydramine interactions. The nitrogen atoms are in blue and the oxygen atoms in red. The carbon atoms are in cyan (HNMT) and in green (inhibitor). The broken lines indicate hydrogen bonds, whose distances are indicated (in Å).
Figure 2
Figure 2
Interactions of HNMT–metoprine. (a) Chemical structure of metoprine (top panel). Lineweaver–Burke plot (bottom panel). The slope of each linear fit was plotted against the concentration of inhibitor and the intercept on the x-axis gave an estimate of Ki (91 nM). (b) Detailed plot of HNMT–diphenhydramine interactions. Replacing the chlorine atom (CL14) in the dichlorophenyl ring with sulfur might improve its interaction with Cys196 (indicated by a double-ended arrow). The simulated-annealing omit electron density map is contoured at 3.5σ above the mean (bottom panel).
Figure 3
Figure 3
Interactions of HNMT–tacrine. (a) Chemical structure of tacrine (left top panel). The simulated-annealing omit electron density map is contoured at 3.5σ above the mean (left bottom panel); Lineweaver–Burke plot (right panel). The estimate Ki is 38.2 nM. Tacrine bound in (b) HNMT, (c) acetylcholinesterase, and (d) carboxylesterase. Broken lines indicate the hydrogen bonds and distances are indicated (in Å).
Figure 4
Figure 4
Interactions of HNMT and amodiaquine. (a) Chemical structure of amodiaquine. (b) Two molecules of amodiaquine bind per HNMT; one binds in the active site pocket and the other in an outer-surface pocket. (c) Detailed plots of HNMT–amodiaquine interactions. The branch structure of amodiaquine is disordered in the outer-surface pocket. (d) A network of hydrogen bonds connects the side-chains of Tyr146, Qln143, Glu28, Asn283, Trp179, and a water molecule. The water molecule interacts with the hydroxyl group of the phenyl ring of amodiaquine. The chlorine atom of the quinoline ring of amodiaquine makes van der Waals contacts with Cγ of Gln94. (e) The two alkylene chains rotate every 120°, and make them look like three branches. The simulated-annealing omit electron density map is contoured at 3.5s above the mean (top panel). Besides the surrounding aromatic rings, one branch interacts (indicated by double-ended arrows) with the side-chain of Cys196 and another interacts with Glu246 (bottom panel). (f) Lineweaver–Burke plot. The estimated Ki is 18.6 nM.
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