2XFQ

Rasagiline-inhibited human monoamine oxidase B in complex with 2-(2- benzofuranyl)-2-imidazoline

Summary for 2XFQ

• Entry DOI: 10.2210/pdb2xfq/pdb
• Related: 1GOS 1H8R 1OJ9 1OJA 1OJB 1OJC 1OJD 1S2Q 1S2Y 1S3B 1S3E 2BK3 2BK4 2BK5 2BYB 2C64 2C65 2C66 2C67 2C70 2C72 2C73 2C75 2C76 2V5Z 2V60 2V61 2VRL 2VRM 2VZ2 2XCG 2XFN 2XFO 2XFP
• Descriptor: Amine oxidase [flavin-containing] B, FLAVIN-ADENINE DINUCLEOTIDE, (1R)-N-(prop-2-en-1-yl)-2,3-dihydro-1H-inden-1-amine, ... (6 entities in total)
• Functional Keywords: flavoprotein, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 120298.01

Authors

Bonivento, D.,Milczek, E.M.,McDonald, G.R.,Binda, C.,Holt, A.,Edmondson, D.E.,Mattevi, A. (deposition date: 2010-05-26, release date: 2010-10-06, Last modification date: 2023-12-20)

Primary citation

Bonivento, D.,Milczek, E.M.,McDonald, G.R.,Binda, C.,Holt, A.,Edmondson, D.E.,Mattevi, A.
Potentiation of ligand binding through cooperative effects in monoamine oxidase B.
J. Biol. Chem., 285:36849-36856, 2010

PubMed Abstract: 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 K(i) of 8.3 ± 0.6 μM, whereas tranylcypromine-inhibited MAO B binds 2-BFI with a K(d) 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 Gln(206) and a "closed conformation" of the side chain of Ile(199), forming a hydrophobic "sandwich" with the side chain of Ile(316) 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 Ile(316) 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.

PubMed: 20855894
DOI: 10.1074/jbc.M110.169482

Experimental method

X-RAY DIFFRACTION (2.2 Å)