3NWB

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

Summary for 3NWB

• Entry DOI: 10.2210/pdb3nwb/pdb
• Related: 3NW9 3NWE 3OZR 3OZS 3OZT
• Descriptor: Catechol O-methyltransferase, MAGNESIUM ION, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: methyltransferase, neurotransmitter degradation, alternative initiation, catecholamine metabolism, cell membrane, magnesium, membrane, metal-binding, phosphoprotein, s-adenosyl-l-methionine, signal-anchor, transmembrane, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (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: 25744.92

Authors

Ehler, A.,Schlatter, D.,Stihle, M.,Benz, J.,Rudolph, M.G. (deposition date: 2010-07-09, release date: 2011-08-03, Last modification date: 2024-03-20)

Primary citation

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, M.G.
Catechol-O-methyltransferase in complex with substituted 3'-deoxyribose bisubstrate inhibitors
Acta Crystallogr.,Sect.D, 68:253-260, 2012

PubMed Abstract: 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 Mg²⁺. 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.

PubMed: 22349227
DOI: 10.1107/S0907444912001138

Experimental method

X-RAY DIFFRACTION (1.3 Å)