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'''Histamine Methyltransferase (Natural Variant I105) Complexed with the Acetylcholinesterase Inhibitor and Altzheimer's Disease Drug Tacrine''' | '''Histamine Methyltransferase (Natural Variant I105) Complexed with the Acetylcholinesterase Inhibitor and Altzheimer's Disease Drug Tacrine''' | ||
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[[Category: Nishibori, M.]] | [[Category: Nishibori, M.]] | ||
[[Category: Sawada, K.]] | [[Category: Sawada, K.]] | ||
[[Category: | [[Category: Classic methyltransferase fold]] | ||
[[Category: | [[Category: Protein-drug complex]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 19:18:09 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 19:18, 3 May 2008
Histamine Methyltransferase (Natural Variant I105) Complexed with the Acetylcholinesterase Inhibitor and Altzheimer's Disease Drug Tacrine
OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Asthma, susceptibility to OMIM:[605238]
About this StructureAbout this Structure
2AOW is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for inhibition of histamine N-methyltransferase by diverse drugs., Horton JR, Sawada K, Nishibori M, Cheng X, J Mol Biol. 2005 Oct 21;353(2):334-44. PMID:16168438 Page seeded by OCA on Sat May 3 19:18:09 2008