1h1d
From Proteopedia
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'''CATECHOL O-METHYLTRANSFERASE''' | '''CATECHOL O-METHYLTRANSFERASE''' | ||
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[[Category: Rodrigues, M L.]] | [[Category: Rodrigues, M L.]] | ||
[[Category: Soares-Da-Silva, P.]] | [[Category: Soares-Da-Silva, P.]] | ||
| - | [[Category: | + | [[Category: Methyltransferase]] |
| - | [[Category: | + | [[Category: Neurotransmitter degradation]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 18:17:39 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 15:17, 2 May 2008
CATECHOL O-METHYLTRANSFERASE
Overview
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 Structure
1H1D is a Single protein structure of sequence from Rattus norvegicus. Full crystallographic information is available from OCA.
Reference
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 Page seeded by OCA on Fri May 2 18:17:39 2008
