1h1d
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CATECHOL O-METHYLTRANSFERASE
OverviewOverview
Catechol-O-methyltransferase (COMT; E.C. 2.1.1.6) is a ubiquitous enzyme, in nature that plays an important role in the metabolism of catechol, neurotransmitters and xenobiotics. In particular, inactivation of drugs, such as L-3,4-dihydroxyphenylalanine (L-DOPA) via O-methylation is of, relevant pharmacological importance, because L-DOPA is currently the most, effective drug used in the treatment of Parkinson's disease. This, justified the interest in developing COMT inhibitors as potential adjuncts, to L-DOPA therapy. The kinetics of inhibition by BIA 3-335, (1-[3,4-dihydroxy-5-nitrophenyl]-3-(N-3'-trifluormethylphenyl)-piperazine-, 1-propanone dihydrochloride) were characterized using recombinant rat, soluble COMT. BIA 3-335 was found to act as a potent, reversible, tight-binding inhibitor of COMT with a K(i) of 6.0 +/- 1.6 nM and, displaying a competitive inhibition toward the substrate binding site and, uncompetitive inhibition toward the S-adenosyl-L-methionine (SAM) binding, site. The 2.0-A resolution crystal structure of COMT in complex with its, cosubstrate SAM and a novel inhibitor BIA 3-335 shows the atomic, interactions between the important residues at the active site and the, inhibitor. This is the first report of a three-dimensional structure, determination of COMT complexed with a potent, reversible, and, tight-binding inhibitor that is expected to have therapeutic applications.
About this StructureAbout this Structure
1H1D is a Single protein structure of sequence from Rattus norvegicus with MG, SAM and BIA as ligands. Active as Catechol O-methyltransferase, with EC number 2.1.1.6 Structure known Active Site: MG1. Full crystallographic information is available from OCA.
ReferenceReference
Kinetics and crystal structure of catechol-o-methyltransferase complex with co-substrate and a novel inhibitor with potential therapeutic application., Bonifacio MJ, Archer M, Rodrigues ML, Matias PM, Learmonth DA, Carrondo MA, Soares-Da-Silva P, Mol Pharmacol. 2002 Oct;62(4):795-805. PMID:12237326
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