3nwb | pdb_00003nwb

Rat COMT in complex with a fluorinated desoxyribose-containing bisubstrate inhibitor avoids hydroxyl group

spinqualitylabelsall models 3nwb, resolution 1.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3nwb is a 1 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 659, CL, MG, NHE, SO4 Related: 3nw9, 3nwe, 3ozr, 3ozs, 3ozt Gene: Comt (Buffalo rat) Activity: Catechol O-methyltransferase, with EC number 2.1.1.6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [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. Publication Abstract from PubMed The biological activity of catechol neurotransmitters such as dopamine in the synapse is modulated by transporters and enzymes. Catechol-O-methyltransferase (COMT; EC 2.1.1.6) inactivates neurotransmitters by catalyzing the transfer of a methyl group from S-adenosylmethionine to catechols in the presence of Mg(2). This pathway also inactivates L-DOPA, the standard therapeutic for Parkinson's disease. Depletion of catechol neurotransmitters in the prefrontal cortex has been linked to schizophrenia. The inhibition of COMT therefore promises improvements in the treatment of these diseases. The concept of bisubstrate inhibitors for COMT has been described previously. Here, ribose-modified bisubstrate inhibitors were studied. Three high-resolution crystal structures of COMT in complex with novel ribose-modified bisubstrate inhibitors confirmed the predicted binding mode but displayed subtle alterations at the ribose-binding site. The high affinity of the inhibitors can be convincingly rationalized from the structures, which document the possibility of removing and/or replacing the ribose 3'-hydroxyl group and provide a framework for further inhibitor design. Catechol-O-methyltransferase in complex with substituted 3'-deoxyribose bisubstrate inhibitors.,Ellermann M, Lerner C, Burgy G, Ehler A, Bissantz C, Jakob-Roetne R, Paulini R, Allemann O, Tissot H, Grunstein D, Stihle M, Diederich F, Rudolph MG Acta Crystallogr D Biol Crystallogr. 2012 Mar;68(Pt 3):253-60. Epub 2012 Feb 14. PMID:22349227 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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