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'''Crystal Structure Analysis of Human Histamine Methyltransferase (Ile105 Polymorphic Variant) Complexed with AdoHcy and Antimalarial Drug Quinacrine''' | '''Crystal Structure Analysis of Human Histamine Methyltransferase (Ile105 Polymorphic Variant) Complexed with AdoHcy and Antimalarial Drug Quinacrine''' | ||
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[[Category: Sawada, K.]] | [[Category: Sawada, K.]] | ||
[[Category: Zhang, X.]] | [[Category: Zhang, X.]] | ||
[[Category: | [[Category: Classic methyltransferase fold]] | ||
[[Category: | [[Category: Polymorphic variant]] | ||
[[Category: | [[Category: Protein-substrate-cofactor complex]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 21:38:27 2008'' | |||
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Revision as of 21:38, 2 May 2008
Crystal Structure Analysis of Human Histamine Methyltransferase (Ile105 Polymorphic Variant) Complexed with AdoHcy and Antimalarial Drug Quinacrine
OverviewOverview
BACKGROUND: Histamine plays important biological roles in cell-to-cell communication; it is a mediator in allergic responses, a regulator of gastric acid secretion, a messenger in bronchial asthma, and a neurotransmitter in the central nervous system. Histamine acts by binding to histamine receptors, and its local action is terminated primarily by methylation. Human histamine N-methyltransferase (HNMT) has a common polymorphism at residue 105 that correlates with the high- (Thr) and low- (Ile) activity phenotypes. RESULTS: Two ternary structures of human HNMT have been determined: the Thr105 variant complexed with its substrate histamine and reaction product AdoHcy and the Ile105 variant complexed with an inhibitor (quinacrine) and AdoHcy. Our steady-state kinetic data indicate that the recombinant Ile105 variant shows 1.8- and 1.3-fold increases in the apparent K(M) for AdoMet and histamine, respectively, and slightly (16%) but consistently lower specific activity as compared to that of the Thr105 variant. These differences hold over a temperature range of 25 degrees C-45 degrees C in vitro. Only at a temperature of 50 degrees C or higher is the Ile105 variant more thermolabile than the Thr105 enzyme. CONCLUSIONS: HNMT has a 2 domain structure including a consensus AdoMet binding domain, where the residue 105 is located on the surface, consistent with the kinetic data that the polymorphism does not affect overall protein stability at physiological temperatures but lowers K(M) values for AdoMet and histamine. The interactions between HNMT and quinacrine provide the first structural insights into a large group of pharmacologic HNMT inhibitors and their mechanisms of inhibition.
DiseaseDisease
Known disease associated with this structure: Asthma, susceptibility to OMIM:[605238]
About this StructureAbout this Structure
1JQE is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons., Horton JR, Sawada K, Nishibori M, Zhang X, Cheng X, Structure. 2001 Sep;9(9):837-49. PMID:11566133 Page seeded by OCA on Fri May 2 21:38:27 2008