3OZS

Rat catechol O-methyltransferase in complex with a catechol-type, trifluoromethyl-imidazolyl-containing inhibitor - humanized form

Summary for 3OZS

• Entry DOI: 10.2210/pdb3ozs/pdb
• Related: 3NW9 3NWB 3NWE 3OZR 3OZT
• Descriptor: Catechol O-methyltransferase, MAGNESIUM ION, N-[(E)-3-[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(trifluoromethyl)imidazol-1-yl]oxolan-2-yl]prop-2-enyl]-2,3-dihydroxy-5-nitro-benzamide, ... (4 entities in total)
• Functional Keywords: methyltransferase, neurotransmitter degradation, alternative initiation, catecholamine metabolism, cell membrane, magnesium, metal-binding, s-adenosyl-l-methionine, signal-anchor, transferase, transmembrane methyltransferase, 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: 25192.98

Authors

Ehler, A.,Schlatter, D.,Stihle, M.,Benz, J.,Rudolph, M.G. (deposition date: 2010-09-27, release date: 2011-03-16, Last modification date: 2024-04-03)

Primary citation

Ellermann, M.,Paulini, R.,Jakob-Roetne, R.,Lerner, C.,Borroni, E.,Roth, D.,Ehler, A.,Schweizer, W.B.,Schlatter, D.,Rudolph, M.G.,Diederich, F.
Molecular Recognition at the Active Site of Catechol-O-methyltransferase (COMT): Adenine Replacements in Bisubstrate Inhibitors
Chemistry, 17:6369-6381, 2011

PubMed Abstract: L-Dopa, the standard therapeutic for Parkinson's disease, is inactivated by the enzyme catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of an activated methyl group from S-adenosylmethionine (SAM) to its catechol substrates, such as L-dopa, in the presence of magnesium ions. The molecular recognition properties of the SAM-binding site of COMT have been investigated only sparsely. Here, we explore this site by structural alterations of the adenine moiety of bisubstrate inhibitors. The molecular recognition of adenine is of special interest due to the great abundance and importance of this nucleobase in biological systems. Novel bisubstrate inhibitors with adenine replacements were developed by structure-based design and synthesized using a nucleosidation protocol introduced by Vorbrüggen and co-workers. Key interactions of the adenine moiety with COMT were measured with a radiochemical assay. Several bisubstrate inhibitors, most notably the adenine replacements thiopyridine, purine, N-methyladenine, and 6-methylpurine, displayed nanomolar IC(50) values (median inhibitory concentration) for COMT down to 6 nM. A series of six cocrystal structures of the bisubstrate inhibitors in ternary complexes with COMT and Mg(2+) confirm our predicted binding mode of the adenine replacements. The cocrystal structure of an inhibitor bearing no nucleobase can be regarded as an intermediate along the reaction coordinate of bisubstrate inhibitor binding to COMT. Our studies show that solvation varies with the type of adenine replacement, whereas among the adenine derivatives, the nitrogen atom at position 1 is essential for high affinity, while the exocyclic amino group is most efficiently substituted by a methyl group.

PubMed: 21538606
DOI: 10.1002/chem.201003648

Experimental method

X-RAY DIFFRACTION (1.44 Å)