1hnn: Difference between revisions
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==CRYSTAL STRUCTURE OF HUMAN PNMT COMPLEXED WITH SK&F 29661 AND ADOHCY(SAH)== | ==CRYSTAL STRUCTURE OF HUMAN PNMT COMPLEXED WITH SK&F 29661 AND ADOHCY(SAH)== | ||
<StructureSection load='1hnn' size='340' side='right' caption='[[1hnn]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='1hnn' size='340' side='right' caption='[[1hnn]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PNMT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PNMT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phenylethanolamine_N-methyltransferase Phenylethanolamine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.28 2.1.1.28] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phenylethanolamine_N-methyltransferase Phenylethanolamine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.28 2.1.1.28] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1hnn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hnn OCA], [http://pdbe.org/1hnn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1hnn RCSB], [http://www.ebi.ac.uk/pdbsum/1hnn PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1hnn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hnn OCA], [http://pdbe.org/1hnn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1hnn RCSB], [http://www.ebi.ac.uk/pdbsum/1hnn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1hnn ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hn/1hnn_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hn/1hnn_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
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</div> | </div> | ||
<div class="pdbe-citations 1hnn" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 1hnn" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 12:14, 10 January 2018
CRYSTAL STRUCTURE OF HUMAN PNMT COMPLEXED WITH SK&F 29661 AND ADOHCY(SAH)CRYSTAL STRUCTURE OF HUMAN PNMT COMPLEXED WITH SK&F 29661 AND ADOHCY(SAH)
Structural highlights
Function[PNMT_HUMAN] Converts noradrenaline to adrenaline. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBACKGROUND: Adrenaline is localized to specific regions of the central nervous system (CNS), but its role therein is unclear because of a lack of suitable pharmacologic agents. Ideally, a chemical is required that crosses the blood-brain barrier, potently inhibits the adrenaline-synthesizing enzyme PNMT, and does not affect other catecholamine processes. Currently available PNMT inhibitors do not meet these criteria. We aim to produce potent, selective, and CNS-active PNMT inhibitors by structure-based design methods. The first step is the structure determination of PNMT. RESULTS: We have solved the crystal structure of human PNMT complexed with a cofactor product and a submicromolar inhibitor at a resolution of 2.4 A. The structure reveals a highly decorated methyltransferase fold, with an active site protected from solvent by an extensive cover formed from several discrete structural motifs. The structure of PNMT shows that the inhibitor interacts with the enzyme in a different mode from the (modeled) substrate noradrenaline. Specifically, the position and orientation of the amines is not equivalent. CONCLUSIONS: An unexpected finding is that the structure of PNMT provides independent evidence of both backward evolution and fold recruitment in the evolution of a complex enzyme from a simple fold. The proposed evolutionary pathway implies that adrenaline, the product of PNMT catalysis, is a relative newcomer in the catecholamine family. The PNMT structure reported here enables the design of potent and selective inhibitors with which to characterize the role of adrenaline in the CNS. Such chemical probes could potentially be useful as novel therapeutics. Getting the adrenaline going: crystal structure of the adrenaline-synthesizing enzyme PNMT.,Martin JL, Begun J, McLeish MJ, Caine JM, Grunewald GL Structure. 2001 Oct;9(10):977-85. PMID:11591352[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References |
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