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3oe4

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==Rat catechol O-methyltransferase in complex with a catechol-type, purine-containing bisubstrate inhibitor - humanized form==
==Rat catechol O-methyltransferase in complex with a catechol-type, purine-containing bisubstrate inhibitor - humanized form==
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<StructureSection load='3oe4' size='340' side='right' caption='[[3oe4]], [[Resolution|resolution]] 1.49&Aring;' scene=''>
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<StructureSection load='3oe4' size='340' side='right'caption='[[3oe4]], [[Resolution|resolution]] 1.49&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3oe4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OE4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OE4 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3oe4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OE4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OE4 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=610:N-[(E)-3-[(2R,3S,4R,5R)-3,4-DIHYDROXY-5-PURIN-9-YL-OXOLAN-2-YL]PROP-2-ENYL]-2,3-DIHYDROXY-5-NITRO-BENZAMIDE'>610</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.49&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3nw9|3nw9]], [[3nwb|3nwb]], [[3nwe|3nwe]], [[3oe5|3oe5]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=610:N-[(E)-3-[(2R,3S,4R,5R)-3,4-DIHYDROXY-5-PURIN-9-YL-OXOLAN-2-YL]PROP-2-ENYL]-2,3-DIHYDROXY-5-NITRO-BENZAMIDE'>610</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Comt ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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=3oe4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oe4 OCA], [https://pdbe.org/3oe4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3oe4 RCSB], [https://www.ebi.ac.uk/pdbsum/3oe4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3oe4 ProSAT]</span></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/Catechol_O-methyltransferase Catechol O-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.6 2.1.1.6] </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=3oe4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oe4 OCA], [http://pdbe.org/3oe4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3oe4 RCSB], [http://www.ebi.ac.uk/pdbsum/3oe4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3oe4 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/COMT_RAT COMT_RAT]] Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.
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[https://www.uniprot.org/uniprot/COMT_RAT COMT_RAT] Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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L-Dopa, the standard therapeutic for Parkinson's disease, is inactivated by the enzyme catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of an activated methyl group from S-adenosylmethionine (SAM) to its catechol substrates, such as L-dopa, in the presence of magnesium ions. The molecular recognition properties of the SAM-binding site of COMT have been investigated only sparsely. Here, we explore this site by structural alterations of the adenine moiety of bisubstrate inhibitors. The molecular recognition of adenine is of special interest due to the great abundance and importance of this nucleobase in biological systems. Novel bisubstrate inhibitors with adenine replacements were developed by structure-based design and synthesized using a nucleosidation protocol introduced by Vorbruggen and co-workers. Key interactions of the adenine moiety with COMT were measured with a radiochemical assay. Several bisubstrate inhibitors, most notably the adenine replacements thiopyridine, purine, N-methyladenine, and 6-methylpurine, displayed nanomolar IC(50) values (median inhibitory concentration) for COMT down to 6 nM. A series of six cocrystal structures of the bisubstrate inhibitors in ternary complexes with COMT and Mg(2+) confirm our predicted binding mode of the adenine replacements. The cocrystal structure of an inhibitor bearing no nucleobase can be regarded as an intermediate along the reaction coordinate of bisubstrate inhibitor binding to COMT. Our studies show that solvation varies with the type of adenine replacement, whereas among the adenine derivatives, the nitrogen atom at position 1 is essential for high affinity, while the exocyclic amino group is most efficiently substituted by a methyl group.
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Molecular recognition at the active site of catechol-O-methyltransferase (COMT): adenine replacements in bisubstrate inhibitors.,Ellermann M, Paulini R, Jakob-Roetne R, Lerner C, Borroni E, Roth D, Ehler A, Schweizer WB, Schlatter D, Rudolph MG, Diederich F Chemistry. 2011 May 27;17(23):6369-81. doi: 10.1002/chem.201003648. Epub, 2011 Apr 27. PMID:21538606<ref>PMID:21538606</ref>
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==See Also==
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*[[Catechol O-methyltransferase 3D structures|Catechol O-methyltransferase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3oe4" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Buffalo rat]]
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[[Category: Large Structures]]
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[[Category: Catechol O-methyltransferase]]
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[[Category: Rattus norvegicus]]
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[[Category: Benz, J]]
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[[Category: Benz J]]
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[[Category: Ehler, A]]
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[[Category: Ehler A]]
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[[Category: Rudolph, M G]]
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[[Category: Rudolph MG]]
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[[Category: Schlatter, D]]
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[[Category: Schlatter D]]
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[[Category: Stihle, M]]
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[[Category: Stihle M]]
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[[Category: Alternative initiation]]
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[[Category: Catecholamine metabolism]]
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[[Category: Cell membrane]]
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[[Category: Magnesium]]
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[[Category: Membrane]]
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[[Category: Metal-binding]]
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[[Category: Methyltransferase]]
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[[Category: Neurotransmitter degradation]]
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[[Category: Phosphoprotein]]
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[[Category: S-adenosyl-l-methionine]]
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[[Category: Signal-anchor]]
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[[Category: Transferase]]
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[[Category: Transferase-transferase inhibitor complex]]
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[[Category: Transmembrane]]
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Current revision

Rat catechol O-methyltransferase in complex with a catechol-type, purine-containing bisubstrate inhibitor - humanized form

PDB ID 3oe4

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