|
|
| Line 1: |
Line 1: |
| | | | |
| | ==human apo COMT== | | ==human apo COMT== |
| - | <StructureSection load='4pyi' size='340' side='right' caption='[[4pyi]], [[Resolution|resolution]] 1.35Å' scene=''> | + | <StructureSection load='4pyi' size='340' side='right'caption='[[4pyi]], [[Resolution|resolution]] 1.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4pyi]] is a 1 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=4PYI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PYI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4pyi]] is a 1 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=4PYI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PYI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4p7k|4p7k]], [[4p7f|4p7f]], [[4p7g|4p7g]], [[4p7j|4p7j]], [[4pyj|4pyj]], [[4pyk|4pyk]], [[4pyl|4pyl]], [[4pym|4pym]], [[4pyn|4pyn]], [[4pyo|4pyo]], [[4pyq|4pyq]]</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=4pyi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pyi OCA], [https://pdbe.org/4pyi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pyi RCSB], [https://www.ebi.ac.uk/pdbsum/4pyi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pyi ProSAT]</span></td></tr> |
| - | <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=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/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>
| + | |
| - | <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=4pyi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pyi OCA], [http://pdbe.org/4pyi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pyi RCSB], [http://www.ebi.ac.uk/pdbsum/4pyi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pyi ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/COMT_HUMAN COMT_HUMAN]] 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. | + | [https://www.uniprot.org/uniprot/COMT_HUMAN COMT_HUMAN] 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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 18: |
| | </div> | | </div> |
| | <div class="pdbe-citations 4pyi" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4pyi" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Catechol O-methyltransferase 3D structures|Catechol O-methyltransferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Catechol O-methyltransferase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Benz, J]] | + | [[Category: Benz J]] |
| - | [[Category: Ehler, A]] | + | [[Category: Ehler A]] |
| - | [[Category: Rudolph, M G]] | + | [[Category: Rudolph MG]] |
| - | [[Category: Schlatter, D]] | + | [[Category: Schlatter D]] |
| - | [[Category: Catecholamine metabolism]]
| + | |
| - | [[Category: Cell membrane]]
| + | |
| - | [[Category: Conformational change]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Methyltransferase]]
| + | |
| - | [[Category: Neurotransmitter degradation]]
| + | |
| - | [[Category: Signal-anchor]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
COMT_HUMAN 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.
Publication Abstract from PubMed
Methylation catalysed by catechol-O-methyltransferase (COMT) is the main pathway of catechol neurotransmitter deactivation in the prefrontal cortex. Low levels of this class of neurotransmitters are held to be causative of diseases such as schizophrenia, depression and Parkinson's disease. Inhibition of COMT may increase neurotransmitter levels, thus offering a route for treatment. Structure-based drug design hitherto seems to be based on the closed enzyme conformation. Here, a set of apo, semi-holo, holo and Michaelis form crystal structures are described that define the conformational space available to COMT and that include likely intermediates along the catalytic pathway. Domain swaps and sizeable loop movements around the active site testify to the flexibility of this enzyme, rendering COMT a difficult drug target. The low affinity of the co-substrate S-adenosylmethionine and the large conformational changes involved during catalysis highlight significant energetic investment to achieve the closed conformation. Since each conformation of COMT is a bona fide target for inhibitors, other states than the closed conformation may be promising to address. Crystallographic data for an alternative avenue of COMT inhibition, i.e. locking of the apo state by an inhibitor, are presented. The set of COMT structures may prove to be useful for the development of novel classes of inhibitors.
Mapping the conformational space accessible to catechol-O-methyltransferase.,Ehler A, Benz J, Schlatter D, Rudolph MG Acta Crystallogr D Biol Crystallogr. 2014 Aug 1;70(Pt 8):2163-74. doi:, 10.1107/S1399004714012917. Epub 2014 Jul 25. PMID:25084335[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ehler A, Benz J, Schlatter D, Rudolph MG. Mapping the conformational space accessible to catechol-O-methyltransferase. Acta Crystallogr D Biol Crystallogr. 2014 Aug 1;70(Pt 8):2163-74. doi:, 10.1107/S1399004714012917. Epub 2014 Jul 25. PMID:25084335 doi:http://dx.doi.org/10.1107/S1399004714012917
|
