TY - JOUR AU - Mattevi, Andrea AB -

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 I199A 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.

TI - Potentiation of Ligand Binding through Cooperative Effects in Monoamine Oxidase B * JF - Journal of Biological Chemistry DO - 10.1074/jbc.m110.169482 DA - 2010-11-19 UR - https://www.deepdyve.com/lp/american-society-for-biochemistry-and-molecular-biology/potentiation-of-ligand-binding-through-cooperative-effects-in-bfQv2asHI0 SP - 36849 EP - 36856 VL - 285 IS - 47 DP - DeepDyve ER -