2aot: Difference between revisions
New page: left|200px<br /> <applet load="2aot" size="450" color="white" frame="true" align="right" spinBox="true" caption="2aot, resolution 1.90Å" /> '''Histamine Methyltra... |
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[[Image:2aot.gif|left|200px]]<br /> | [[Image:2aot.gif|left|200px]]<br /><applet load="2aot" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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'''Histamine Methyltransferase Complexed with the Antihistamine Drug Diphenhydramine'''<br /> | '''Histamine Methyltransferase Complexed with the Antihistamine Drug Diphenhydramine'''<br /> | ||
==Overview== | ==Overview== | ||
In mammals, histamine action is terminated through metabolic inactivation | 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. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
2AOT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 2PM and SAH as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Histamine_N-methyltransferase Histamine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.8 2.1.1.8] Full crystallographic information is available from [http:// | 2AOT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=2PM:'>2PM</scene> and <scene name='pdbligand=SAH:'>SAH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Histamine_N-methyltransferase Histamine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.8 2.1.1.8] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AOT OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Cheng, X.]] | [[Category: Cheng, X.]] | ||
[[Category: Horton, J | [[Category: Horton, J R.]] | ||
[[Category: Nishibori, M.]] | [[Category: Nishibori, M.]] | ||
[[Category: Sawada, K.]] | [[Category: Sawada, K.]] | ||
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[[Category: protein-drug complex]] | [[Category: protein-drug complex]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:29:25 2008'' | ||
Revision as of 17:29, 21 February 2008
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Histamine Methyltransferase Complexed with the Antihistamine Drug Diphenhydramine
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
2AOT is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Histamine N-methyltransferase, with EC number 2.1.1.8 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
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