2XCG

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

Summary for 2XCG

• Entry DOI: 10.2210/pdb2xcg/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
• Descriptor: Amine oxidase [flavin-containing] B, [[(2R,3S,4S)-5-[(4AS)-7,8-DIMETHYL-2,4-DIOXO-4A,5-DIHYDROBENZO[G]PTERIDIN-10-YL]-2,3,4-TRIHYDROXY-PENTOXY]-HYDROXY-PHOSPHORYL] [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL HYDROGEN PHOSPHATE, 3-PHENYLPROPANAL, ... (6 entities in total)
• Functional Keywords: flavoprotein, maob, mitochondrion, oxidoreductase, transmembrane
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 120560.44

Authors

Bonivento, D.,Milczek, E.M.,McDonald, G.R.,Binda, C.,Holt, A.,Edmondson, D.E.,Mattevi, A. (deposition date: 2010-04-23, release date: 2010-10-06, Last modification date: 2024-11-06)

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 (1.9 Å)