6RKB

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

Summary for 6RKB

• Entry DOI: 10.2210/pdb6rkb/pdb
• Descriptor: Amine oxidase [flavin-containing] B, FLAVIN-ADENINE DINUCLEOTIDE, 4-[(~{E})-2-(4-fluorophenyl)ethenyl]-1-[(~{E})-prop-1-enyl]piperidine, ... (5 entities in total)
• Functional Keywords: monoamine oxidase, drug target, neurodegeneration, flavin, isomer, mitochondrial membrane, flavoprotein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 120410.34

Authors

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. (deposition date: 2019-04-30, release date: 2020-01-29, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)