In human, catechol-O-methyltransferase (COMT: E.C. 18.104.22.168) is responsible for metabolism of catechol neurotransmitter and xenobiotics. The main clinical interest in COMT results from the possibility of using COMT inhibitors as adjuncts in the therapy of Parkinson's disease (PD) with l-DOPA. COMT is therefore a target for inhibitor development aiming at PD treatment and has been submitted to extensive structure-based drug design. Recently reported inhibitors have nitrocatechol structure that may inhibit oxidative phosphorylation and uncouple mitochondrial energy production. This work reports the first crystallographic study of Rat COMT complexed with non-nitrocatechol inhibitor. Analysis of the structural differences among the previously reported inhibitor complexes, coumarine-based inhibitor (4-phenyl-7, 8-dihydroxycoumarine: 4PCM) bound structure provides the explanation for inhibitor binding and can be used for future inhibitor design.
Crystal structures of rat catechol-O-methyltransferase complexed with coumarine-based inhibitor.,Tsuji E, Okazaki K, Takeda K Biochem Biophys Res Commun. 2009 Jan 16;378(3):494-7. Epub 2008 Dec 3. PMID:19056347
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↑ Tsuji E, Okazaki K, Takeda K. Crystal structures of rat catechol-O-methyltransferase complexed with coumarine-based inhibitor. Biochem Biophys Res Commun. 2009 Jan 16;378(3):494-7. Epub 2008 Dec 3. PMID:19056347 doi:S0006-291X(08)02267-5