2aox: Difference between revisions

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-[[Image:2aox.gif|left|200px]]<br />
-<applet load="2aox" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="2aox, resolution 3.12&Aring;" />
-'''Histamine Methyltransferase (Primary Variant T105) Complexed with the Acetylcholinesterase Inhibitor and Altzheimer's Disease Drug Tacrine'''<br />
-==Overview==
+==Histamine Methyltransferase (Primary Variant T105) Complexed with the Acetylcholinesterase Inhibitor and Altzheimer's Disease Drug Tacrine==
-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.
+<StructureSection load='2aox' size='340' side='right'caption='[[2aox]], [[Resolution|resolution]] 3.12&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2aox]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AOX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AOX FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.12&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=THA:TACRINE'>THA</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2aox FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2aox OCA], [https://pdbe.org/2aox PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2aox RCSB], [https://www.ebi.ac.uk/pdbsum/2aox PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2aox ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/HNMT_HUMAN HNMT_HUMAN] Inactivates histamine by N-methylation. Plays an important role in degrading histamine and in regulating the airway response to histamine.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ao/2aox_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2aox ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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==
+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<ref>PMID:16168438</ref>
-Known disease associated with this structure: Asthma, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605238 605238]]
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-AOX 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 THA as [http://en.wikipedia.org/wiki/ligand ligand]. 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2AOX OCA].
+</div>
+<div class="pdbe-citations 2aox" style="background-color:#fffaf0;"></div>
-==Reference==
+== References ==
-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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16168438 16168438]
+<references/>
-[[Category: Histamine N-methyltransferase]]
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Cheng, X.]]
+[[Category: Cheng X]]
-[[Category: Horton, J.R.]]
+[[Category: Horton JR]]
-[[Category: Nishibori, M.]]
+[[Category: Nishibori M]]
-[[Category: Sawada, K.]]
+[[Category: Sawada K]]
-[[Category: THA]]
-[[Category: classic methyltransferase fold]]
-[[Category: protein-drug complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:53:31 2007''