6LFE
Rat-COMT, Nitecapone,SAM and Mg bond
Summary for 6LFE
| Entry DOI | 10.2210/pdb6lfe/pdb |
| Descriptor | Catechol O-methyltransferase, S-ADENOSYLMETHIONINE, 3-(3,4-dihydroxy-5-nitrobenzylidene)pentane-2,4-dione, ... (7 entities in total) |
| Functional Keywords | enzyme s-adenosylmethionone catechol, catecholamine, transferase |
| Biological source | Rattus norvegicus (Rat) |
| Total number of polymer chains | 1 |
| Total formula weight | 25936.92 |
| Authors | Takebe, K.,Iijima, H.,Suzuki, M. (deposition date: 2019-12-02, release date: 2020-03-04, Last modification date: 2023-11-22) |
| Primary citation | Iijima, H.,Takebe, K.,Suzuki, M.,Kobayashi, H.,Takamiya, T.,Saito, H.,Niwa, N.,Kuwada-Kusunose, T. Crystal Structure of Catechol O-Methyltransferase Complexed with Nitecapone. Chem Pharm Bull (Tokyo), 68:447-451, 2020 Cited by PubMed Abstract: Catechol O-methyltransferase (COMT) is known as an important drug-target protein in the field of Parkinson's disease. All clinically approved COMT inhibitors bring a 5-substituted-3-nitrocatechol ring as a pharmacophore, and they bind to COMT with S-adenosylmethionine (SAM) and an Mg ion to form a quaternary complex (COMT/SAM/Mg/inhibitor). However, structural information about such quaternary complexes is only available for a few inhibitors. Here, a new crystal structure of COMT complexed with nitecapone (5), SAM and Mg is revealed. Comparison of the structures of these complexes indicates that conformation of the catechol binding pocket is almost constant regardless of structure of the inhibitors. The only restriction of the side chain of inhibitors (i.e., the substituent at the 5-position of 3-nitrocatechol) seems to be that it does not make steric repulsion with COMT. However, recent crystallographic and biochemical studies suggest that COMT is a flexible protein, and its conformational flexibility seems crucial for its catalytic process. Based on this information, implications of these quaternary inhibitor complexes were investigated. Met 40 in the α2α3-loop makes atomic contacts with SAM or S-adenosylhomocysteine and the 3-position of the catechol inhibitor. This interaction seems to play a critical role in the affinity of the inhibitor and to stabilize the COMT/SAM/Mg/nitrocatechol inhibitor complex by fixing the flexible α2α3-loop. PubMed: 32378542DOI: 10.1248/cpb.c20-00011 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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