1jqe: Difference between revisions
New page: left|200px<br /> <applet load="1jqe" size="450" color="white" frame="true" align="right" spinBox="true" caption="1jqe, resolution 1.91Å" /> '''Crystal Structure A... |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:1jqe.gif|left|200px]]<br /> | [[Image:1jqe.gif|left|200px]]<br /><applet load="1jqe" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1jqe" size=" | |||
caption="1jqe, resolution 1.91Å" /> | caption="1jqe, resolution 1.91Å" /> | ||
'''Crystal Structure Analysis of Human Histamine Methyltransferase (Ile105 Polymorphic Variant) Complexed with AdoHcy and Antimalarial Drug Quinacrine'''<br /> | '''Crystal Structure Analysis of Human Histamine Methyltransferase (Ile105 Polymorphic Variant) Complexed with AdoHcy and Antimalarial Drug Quinacrine'''<br /> | ||
==Overview== | ==Overview== | ||
BACKGROUND: Histamine plays important biological roles in cell-to-cell | 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. | ||
==Disease== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
1JQE 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 SAH, QUN and UNX 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:// | 1JQE 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=SAH:'>SAH</scene>, <scene name='pdbligand=QUN:'>QUN</scene> and <scene name='pdbligand=UNX:'>UNX</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=1JQE OCA]. | ||
==Reference== | ==Reference== | ||
| Line 19: | Line 18: | ||
[[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.]] | ||
| Line 30: | Line 29: | ||
[[Category: protein-substrate-cofactor complex]] | [[Category: protein-substrate-cofactor complex]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:25:32 2008'' | ||
Revision as of 14:25, 21 February 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 with , and as ligands. Active as Histamine N-methyltransferase, with EC number 2.1.1.8 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 Thu Feb 21 13:25:32 2008