4CRT

Crystal structure of human monoamine oxidase B in complex with the multi-target inhibitor ASS234

Summary for 4CRT

• Entry DOI: 10.2210/pdb4crt/pdb
• Descriptor: AMINE OXIDASE [FLAVIN-CONTAINING] B, FLAVIN-ADENINE DINUCLEOTIDE, (E)-N-methyl-N-[[1-methyl-5-[3-[1-(phenylmethyl)piperidin-4-yl]propoxy]indol-2-yl]methyl]prop-1-en-1-amine, ... (4 entities in total)
• Functional Keywords: oxidoreductase, enzyme, flavin, drug design, alzheimer's disease
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Mitochondrion outer membrane; Single-pass type IV membrane protein; Cytoplasmic side: P27338
• Total number of polymer chains: 2
• Total formula weight: 120137.84

Authors

Esteban, G.,Allan, J.,Samadi, A.,Mattevi, A.,Unzeta, M.,Marco-Contelles, J.,Binda, C.,Ramsay, R.R. (deposition date: 2014-02-28, release date: 2014-04-02, Last modification date: 2024-11-13)

Primary citation

Esteban, G.,Allan, J.,Samadi, A.,Mattevi, A.,Unzeta, M.,Marco-Contelles, J.,Binda, C.,Ramsay, R.R.
Kinetic and Structural Analysis of the Irreversible Inhibition of Human Monoamine Oxidases by Ass234, a Multi-Target Compound Designed for Use in Alzheimer'S Disease.
Biochim.Biophys.Acta, 1844:1104-, 2014

PubMed Abstract: Monoamine oxidases (MAO) and cholinesterases are validated targets in the design of drugs for the treatment of Alzheimer's disease. The multi-target compound N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (ASS234), bearing the MAO-inhibiting propargyl group attached to a donepezil moiety that inhibits cholinesterases, retained activity against human acetyl- and butyryl-cholinesterases. The inhibition of MAO A and MAO B by ASS234 was characterized and compared to other known MAO inhibitors. ASS234 was almost as effective as clorgyline (kinact/KI=3×10(6) min(-1)M(-1)) and was shown by structural studies to form the same N5 covalent adduct with the FAD cofactor.

PubMed: 24642166
DOI: 10.1016/J.BBAPAP.2014.03.006

Experimental method

X-RAY DIFFRACTION (1.8 Å)