6RKB

Crystal structure of human monoamine oxidase B in complex with styrylpiperidine analogue 1

6RKB の概要

• エントリーDOI: 10.2210/pdb6rkb/pdb
• 分子名称: Amine oxidase [flavin-containing] B, FLAVIN-ADENINE DINUCLEOTIDE, 4-[(~{E})-2-(4-fluorophenyl)ethenyl]-1-[(~{E})-prop-1-enyl]piperidine, ... (5 entities in total)
• 機能のキーワード: monoamine oxidase, drug target, neurodegeneration, flavin, isomer, mitochondrial membrane, 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: 120410.34

構造登録者

Iacovino, L.G.,Knez, D.,Colettis, N.,Sova, M.,Pislar, A.,Higgs, J.,Kamecki, F.,Mangialavori, I.,Dolsak, A.,Zakelj, S.,Trontelj, J.,Kos, J.,Marder, N.M.,Gobec, S.,Binda, C. (登録日: 2019-04-30, 公開日: 2020-01-29, 最終更新日: 2024-10-23)

主引用文献

Knez, D.,Colettis, N.,Iacovino, L.G.,Sova, M.,Pislar, A.,Konc, J.,Lesnik, S.,Higgs, J.,Kamecki, F.,Mangialavori, I.,Dolsak, A.,Zakelj, S.,Trontelj, J.,Kos, J.,Binda, C.,Marder, M.,Gobec, S.
Stereoselective Activity of 1-Propargyl-4-styrylpiperidine-like Analogues That Can Discriminate between Monoamine Oxidase Isoforms A and B.
J.Med.Chem., 63:1361-1387, 2020

PubMed Abstract: The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of and -1-propargyl-4-styrylpiperidines. While the isomers are potent human MAO-A inhibitors, the analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed in mouse brain homogenates, and additional studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of / isomers that can discriminate between structurally related enzyme isoforms.

PubMed: 31917923
DOI: 10.1021/acs.jmedchem.9b01886

実験手法

X-RAY DIFFRACTION (2.3 Å)