|2xfq, resolution 2.20Å ()|
|Ligands:||, , ,|
|Related:||2c67, 1oja, 2v5z, 1s3e, 2c73, 1ojb, 2v60, 2byb, 2vrm, 2c65, 2c64, 2xcg, 1oj9, 1ojd, 2vz2, 1s3b, 2c66, 2bk4, 2bk5, 1h8r, 2c70, 2c75, 2bk3, 2v61, 2c72, 1s2y, 1gos, 1s2q, 2c76, 2vrl, 1ojc, 2xfo, 2xfn, 2xfp|
rasagiline-inhibited human monoamine oxidase B in complex with 2-(2- benzofuranyl)-2-imidazoline
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 muM whereas tranylcypromine-inhibited MAO B binds 2-BFI with a Kd of 9+/-2 nM, representing an increase in binding energy Delta(DeltaG) 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.
Potentiation of ligand binding through cooperative effects in monoamine oxidase B., Bonivento D, Milczek EM, McDonald GR, Binda C, Holt A, Edmondson DE, Mattevi A, J Biol Chem. 2010 Sep 20. PMID:20855894
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.