6lfe | pdb_00006lfe

Rat-COMT, Nitecapone,SAM and Mg bond

spinqualitylabelsall models 6lfe, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6lfe is a 1 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: EAO, IPA, MG, PEG, SAM 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 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(2+) ion to form a quaternary complex (COMT/SAM/Mg(2+)/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(2+) 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 alpha2alpha3-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(2+)/nitrocatechol inhibitor complex by fixing the flexible alpha2alpha3-loop. Crystal Structure of Catechol O-Methyltransferase Complexed with Nitecapone.,Iijima H, Takebe K, Suzuki M, Kobayashi H, Takamiya T, Saito H, Niwa N, Kuwada-Kusunose T Chem Pharm Bull (Tokyo). 2020;68(5):447-451. doi: 10.1248/cpb.c20-00011. PMID:32378542 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA