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| | <StructureSection load='2g8n' size='340' side='right'caption='[[2g8n]], [[Resolution|resolution]] 2.15Å' scene=''> | | <StructureSection load='2g8n' size='340' side='right'caption='[[2g8n]], [[Resolution|resolution]] 2.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2g8n]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G8N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2G8N FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2g8n]] 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=2G8N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2G8N FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F83:(3R)-N-(4-CHLOROPHENYL)-3-(HYDROXYMETHYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE'>F83</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1hnn|1hnn]], [[1nji|1nji]], [[1n7j|1n7j]], [[1yz3|1yz3]], [[2an3|2an3]], [[2an4|2an4]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F83:(3R)-N-(4-CHLOROPHENYL)-3-(HYDROXYMETHYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE'>F83</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Phenylethanolamine_N-methyltransferase Phenylethanolamine N-methyltransferase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=2g8n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g8n OCA], [https://pdbe.org/2g8n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2g8n RCSB], [https://www.ebi.ac.uk/pdbsum/2g8n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2g8n ProSAT]</span></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=2g8n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g8n OCA], [https://pdbe.org/2g8n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2g8n RCSB], [https://www.ebi.ac.uk/pdbsum/2g8n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2g8n ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/PNMT_HUMAN PNMT_HUMAN]] Converts noradrenaline to adrenaline.
| + | [https://www.uniprot.org/uniprot/PNMT_HUMAN PNMT_HUMAN] Converts noradrenaline to adrenaline. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Phenylethanolamine N-methyltransferase]]
| + | [[Category: Drinkwater N]] |
| - | [[Category: Drinkwater, N]] | + | [[Category: Gee CL]] |
| - | [[Category: Gee, C L]] | + | [[Category: Martin JL]] |
| - | [[Category: Martin, J L]] | + | |
| - | [[Category: Methyltransferase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| 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 PubMed
3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH- could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH- with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the alpha2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT Ki = 1.3 microM) is the most potent compound in this series and is quite selective for PNMT versus the alpha2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT Ki = 0.13 microM). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH- is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.
Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase.,Grunewald GL, Seim MR, Regier RC, Martin JL, Gee CL, Drinkwater N, Criscione KR J Med Chem. 2006 Sep 7;49(18):5424-33. PMID:16942016[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Grunewald GL, Seim MR, Regier RC, Martin JL, Gee CL, Drinkwater N, Criscione KR. Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase. J Med Chem. 2006 Sep 7;49(18):5424-33. PMID:16942016 doi:http://dx.doi.org/10.1021/jm060466d
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