1H1D

Catechol O-Methyltransferase

Summary for 1H1D

• Entry DOI: 10.2210/pdb1h1d/pdb
• Related: 1VID
• Descriptor: CATECHOL-O-METHYLTRANSFERASE, MAGNESIUM ION, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• Functional Keywords: transferase, methyltransferase, neurotransmitter degradation
• Biological source: RATTUS NORVEGICUS (NORWAY RAT)
• Cellular location: Isoform 2: Cytoplasm. Isoform 1: Cell membrane; Single-pass type II membrane protein; Extracellular side: P22734
• Total number of polymer chains: 1
• Total formula weight: 25634.53

Authors

Archer, M.,Rodrigues, M.L.,Matias, P.M.,Bonifacio, M.J.,Learmonth, D.A.,Soares-da-Silva, P.,Carrondo, M.A. (deposition date: 2002-07-12, release date: 2003-07-17, Last modification date: 2023-12-13)

Primary citation

Bonifacio, M.J.,Archer, M.,Rodrigues, M.L.,Matias, P.M.,Learmonth, D.A.,Carrondo, M.A.,Soares-da-Silva, P.
Kinetics and Crystal Structure of Catechol-O-Methyltransferase Complex with Co-Substrate and a Novel Inhibitor with Potential Therapeutic Application
Mol.Pharmacol., 62:795-, 2002

PubMed Abstract: 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.

PubMed: 12237326
DOI: 10.1124/MOL.62.4.795

Experimental method

X-RAY DIFFRACTION (2 Å)