7XJB

Rat-COMT, opicapone,SAM and Mg bond

Summary for 7XJB

• Entry DOI: 10.2210/pdb7xjb/pdb
• Descriptor: Catechol O-methyltransferase, S-ADENOSYLMETHIONINE, Opicapone, ... (7 entities in total)
• Functional Keywords: enzyme s-adenosylmethionone catechol, catecholamine, transferase
• Biological source: Rattus norvegicus (Norway rat)
• Total number of polymer chains: 4
• Total formula weight: 103210.02

Authors

Takebe, K.,Iijima, H.,Suzuki, M.,Kuwada-Kusunose, T. (deposition date: 2022-04-15, release date: 2023-05-31, Last modification date: 2023-11-29)

Primary citation

Takebe, K.,Suzuki, M.,Kuwada-Kusunose, T.,Shirai, S.,Fukuzawa, K.,Takamiya, T.,Uzawa, N.,Iijima, H.
Structural and Computational Analyses of the Unique Interactions of Opicapone in the Binding Pocket of Catechol O -Methyltransferase: A Crystallographic Study and Fragment Molecular Orbital Analyses.
J.Chem.Inf.Model., 63:4468-4476, 2023

PubMed Abstract: A third-generation inhibitor of catechol -methyltransferase (COMT), opicapone (), has the 3-nitrocatechol scaffold as do the second-generation inhibitors such as entacapone () and tolcapone (), but only can sustainably inhibit COMT activity making it suitable for a once-daily regimen. These improvements should be attributed to the optimized sidechain moiety (oxidopyridyloxadiazolyl group) of substituted at the 5-position of the 3-nitrocatechol ring. We analyzed the role of the sidechain moiety by solving the crystal structures of COMT/-adenosylmethionine (SAM)/Mg/ and COMT/-adenosylhomocysteine (SAH)/Mg/ complexes. Fragment molecular orbital (FMO) calculations elucidated that the dispersion interaction between the sidechains of Leu 198 and Met 201 on the β6β7-loop and the oxidopyridine ring of were unique and important in both complexes. In contrast, the catechol binding site made a remarkable difference in the sidechain conformation of Lys 144. The ε-amino group of Lys 144 was outside of the catalytic pocket and was replaced by a water molecule in the COMT/SAH/Mg/ complex. No nitrocatechol inhibitor has ever been reported to make a complex with COMT and SAH. Thus, the conformational change of Lys 144 found in the COMT/SAH/Mg/ complex is the first crystallographic evidence that supports the role of Lys 144 as a catalytic base to take out a proton ion from the reaction site to the outside of the enzyme. The fact that generated a complex with SAH and COMT also suggests that could inhibit COMT twofold, as a typical substrate mimic competitive inhibitor and as a product-inhibition enhancer.

PubMed: 37436881
DOI: 10.1021/acs.jcim.3c00331

Experimental method

X-RAY DIFFRACTION (2.6 Å)