6FWC

Crystal structure of human monoamine oxidase B (MAO B) in complex with fluorophenyl-chromone-carboxamide

6FWC の概要

• エントリーDOI: 10.2210/pdb6fwc/pdb
• 分子名称: Amine oxidase [flavin-containing] B, FLAVIN-ADENINE DINUCLEOTIDE, ~{N}-(3-fluorophenyl)-4-oxidanylidene-chromene-3-carboxamide, ... (6 entities in total)
• 機能のキーワード: parkinson's disease, drug design, chromone, inhibitor, flavoprotein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 120670.36

構造登録者

Reis, J.,Manzella, N.,Cagide, F.,Mialet-Perez, J.,Uriarte, E.,Parini, A.,Borges, F.,Binda, C. (登録日: 2018-03-06, 公開日: 2018-04-25, 最終更新日: 2024-10-16)

主引用文献

Reis, J.,Manzella, N.,Cagide, F.,Mialet-Perez, J.,Uriarte, E.,Parini, A.,Borges, F.,Binda, C.
Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis.
J. Med. Chem., 61:4203-4212, 2018

PubMed Abstract: Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson's disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6-1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with K values of 55, 17, and 31 nM for N-(3',4'-dimethylphenyl)-4-oxo-4 H-chromene-3-carboxamide (1), N-(3'-chlorophenyl)-4-oxo-4 H-chromene-3-carboxamide (2), and N-(3'-fluorophenyl)-4-oxo-4 H-chromene-3-carboxamide (3), respectively. These compounds were also 1000-fold more effective than l-deprenyl in reducing the cellular levels of reactive oxygen species (ROS).

PubMed: 29648817
DOI: 10.1021/acs.jmedchem.8b00357

実験手法

X-RAY DIFFRACTION (1.7 Å)