4dm3

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==Crystal structure of human PNMT in complex adohcy, resorcinol and imidazole==
==Crystal structure of human PNMT in complex adohcy, resorcinol and imidazole==
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<StructureSection load='4dm3' size='340' side='right' caption='[[4dm3]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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<StructureSection load='4dm3' size='340' side='right'caption='[[4dm3]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4dm3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DM3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DM3 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4dm3]] 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=4DM3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DM3 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=RCO:RESORCINOL'>RCO</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=RCO:RESORCINOL'>RCO</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3kpy|3kpy]]</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4dm3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dm3 OCA], [https://pdbe.org/4dm3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dm3 RCSB], [https://www.ebi.ac.uk/pdbsum/4dm3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dm3 ProSAT]</span></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PNMT, PENT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<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>
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<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=4dm3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dm3 OCA], [http://pdbe.org/4dm3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dm3 RCSB], [http://www.ebi.ac.uk/pdbsum/4dm3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dm3 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/PNMT_HUMAN PNMT_HUMAN]] Converts noradrenaline to adrenaline.
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[[https://www.uniprot.org/uniprot/PNMT_HUMAN PNMT_HUMAN]] Converts noradrenaline to adrenaline.
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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CNS (central nervous system) adrenaline (epinephrine) is implicated in a wide range of physiological and pathological conditions. PNMT (phenylethanolamine N-methyltransferase) catalyses the final step in the biosynthesis of adrenaline, the conversion of noradrenaline (norepinephrine) to adrenaline by methylation. To help elucidate the role of CNS adrenaline, and to develop potential drug leads, potent, selective and CNS-active inhibitors are required. The fragment screening approach has advantages over other lead discovery methods including high hit rates, more efficient hits and the ability to sample chemical diversity more easily. In the present study we applied fragment-based screening approaches to the enzyme PNMT. We used crystallography as the primary screen and identified 12 hits from a small commercial library of 384 drug-like fragments. The hits include nine chemicals with two fused rings and three single-ring chemical systems. Eight of the hits come from three chemical classes: benzimidazoles (a known class of PNMT inhibitor), purines and quinolines. Nine of the hits have measurable binding affinities (~5-700 muM) as determined by isothermal titration calorimetry and all nine have ligand efficiencies of 0.39 kcal/mol per heavy atom or better (1 kcal approximately 4.184 kJ). We synthesized five elaborated benzimidazole compounds and characterized their binding to PNMT, showing for the first time how this class of inhibitors interact with the noradrenaline-binding site. Finally, we performed a pilot study with PNMT for fragment-based screening by MS showing that this approach could be used as a fast and efficient first-pass screening method prior to characterization of binding mode and affinity of hits.
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The aim of fragment-based drug design (FBDD) is to identify molecular fragments that bind to alternate subsites within a given binding pocket leading to cooperative binding when linked. In this study, the binding of fragments to human phenylethanolamine N-methyltransferase is used to illustrate how (a) current protocols may fail to detect fragments that bind cooperatively, (b) theoretical approaches can be used to validate potential hits, and (c) apparent false positives obtained when screening against cocktails of fragments may in fact indicate promising leads.
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Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors.,Drinkwater N, Vu H, Lovell KM, Criscione KR, Collins BM, Prisinzano TE, Poulsen SA, McLeish MJ, Grunewald GL, Martin JL Biochem J. 2010 Oct 1;431(1):51-61. PMID:20642456<ref>PMID:20642456</ref>
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Missing fragments: detecting cooperative binding in fragment-based drug design.,Nair PC, Malde AK, Drinkwater N, Mark AE ACS Med Chem Lett. 2012 Feb 14;3(4):322-6. doi: 10.1021/ml300015u. eCollection, 2012 Apr 12. PMID:24900472<ref>PMID:24900472</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 4dm3" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 4dm3" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Phenylethanolamine N-methyltransferase|Phenylethanolamine N-methyltransferase]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Phenylethanolamine N-methyltransferase]]
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[[Category: Large Structures]]
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[[Category: Malde, A K]]
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[[Category: Malde AK]]
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[[Category: Mark, A E]]
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[[Category: Mark AE]]
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[[Category: Nair, P C]]
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[[Category: Nair PC]]
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[[Category: Transferase]]
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Revision as of 08:27, 21 September 2022

Crystal structure of human PNMT in complex adohcy, resorcinol and imidazole

PDB ID 4dm3

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