5k0b: Difference between revisions
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==Crystal Structure of COMT in complex with 2,4-dimethyl-5-[3-(1-phenylethyl)-1H-pyrazol-5-yl]-1,3-thiazole== | ==Crystal Structure of COMT in complex with 2,4-dimethyl-5-[3-(1-phenylethyl)-1H-pyrazol-5-yl]-1,3-thiazole== | ||
<StructureSection load='5k0b' size='340' side='right' caption='[[5k0b]], [[Resolution|resolution]] 2.36Å' scene=''> | <StructureSection load='5k0b' size='340' side='right'caption='[[5k0b]], [[Resolution|resolution]] 2.36Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5k0b]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K0B OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5k0b]] is a 8 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=5K0B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5K0B FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6PS:2,4-DIMETHYL-5-{3-[(1R)-1-PHENYLETHYL]-1H-PYRAZOL-5-YL}-1,3-THIAZOLE'>6PS</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CXS:3-CYCLOHEXYL-1-PROPYLSULFONIC+ACID'>CXS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.36Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6PS:2,4-DIMETHYL-5-{3-[(1R)-1-PHENYLETHYL]-1H-PYRAZOL-5-YL}-1,3-THIAZOLE'>6PS</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CXS:3-CYCLOHEXYL-1-PROPYLSULFONIC+ACID'>CXS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5k0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k0b OCA], [https://pdbe.org/5k0b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5k0b RCSB], [https://www.ebi.ac.uk/pdbsum/5k0b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5k0b ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [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. | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed the identification of structurally related fragments of high ligand efficiency and with activity on the described orthogonal assays. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported. These compounds represent a novel series of potent COMT inhibitors that might be further optimized to new drugs useful for the treatment of Parkinson's disease, as adjuncts in levodopa based therapy, or for the treatment of schizophrenia. | |||
Design of Potent and Druglike Nonphenolic Inhibitors for Catechol O-Methyltransferase Derived from a Fragment Screening Approach Targeting the S-Adenosyl-l-methionine Pocket.,Lerner C, Jakob-Roetne R, Buettelmann B, Ehler A, Rudolph M, Rodriguez Sarmiento RM J Med Chem. 2016 Oct 14. PMID:27685665<ref>PMID:27685665</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5k0b" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Catechol O-methyltransferase 3D structures|Catechol O-methyltransferase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Rattus norvegicus]] | ||
[[Category: | [[Category: Ehler A]] | ||
[[Category: | [[Category: Rodriguez-Sarmiento RM]] | ||
[[Category: | [[Category: Rudolph MG]] | ||