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Potentiation of ligand binding through cooperative effects in monoamine oxidase B

BONIVENTO, DANIELE;BINDA, CLAUDIA;MATTEVI, ANDREA
2010-01-01
2010
Biochemistry & Biophysics focuses on the structure and chemistry of biomolecules and covers all aspects of basic biochemistry/biophysics, including molecular structure, enzyme kinetics and protein-protein interaction; this category also contains cross-disciplinary resources focused on a specific class of biological molecules, e.g., nucleic acids, steroids, magnesium, growth factors, free radicals, bio-membranes, and peptides. Excluded are resources dealing with the application of biochemical techniques to specific topics listed elsewhere in CC/LS. Resources with a strong emphasis on the integration of biochemical pathways (such as signal transduction or molecular motors) at the cellular level are placed in the Cell & Developmental Biology category.
JOURNAL OF BIOLOGICAL CHEMISTRY
sì
WOS:000284146100025
2-s2.0-78049530845
Sì, ma tipo non specificato
Inglese
Internazionale
STAMPA
285
47
36849
36856
8
20855894
Crystallographic and biochemical studies have been employed to identify the binding site and mechanism for potentiation of imidazoline-binding in human monoamine oxidase B (MAO B). 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) inhibits recombinant human MAO B with a Ki of 8.3±0.6 μM whereas tranylcypromine-inhibited MAO B binds 2-BFI with a Kd of 9±2 nM, representing an increase in binding energy Δ(ΔG) of -3.9 kcal/mol. Crystal structures show the imidazoline ligand bound in a site that is distinct from the substrate-binding cavity. Contributions to account for the increase in binding affinity upon tranylcypromine inhibition include a conformational change in the side chain of Gln206 and a "closed conformation" of the side chain of Ile199, forming a hydrophobic "sandwich" with the side chain of Ile316 on each face of the benzofuran ring of 2-BFI. Data with the Ile199Ala mutant of human MAO B and failure to observe a similar binding potentiation with rat MAO B, where Ile316 is replaced with a Val residue, support an allosteric mechanism where the increased binding affinity of 2-BFI results from a cooperative increase in H-bond strength through formation of a more hydrophobic milieu. These insights should prove valuable in the design of high affinity and specific reversible MAO B inhibitors.
drug design; neurotransmitter; Parkinson's disease
7
info:eu-repo/semantics/article
262
Bonivento, Daniele; Milczek, Em; Mcdonald, Gr; Binda, Claudia; Holt, A; Edmondson, De; Mattevi, Andrea
1 Contributo su Rivista::1.1 Articolo in rivista
none
1.1 Articolo in rivista
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/218483
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