2XFQ: rasagiline-inhibited human monoamine oxidase B in complex with 2-(2- benzofuranyl)-2-imidazoline

Citation:
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 muM, whereas tranylcypromine-inhibited MAO B binds 2-BFI with a K(d) 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 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.
PDB ID: 2XFQDownload
MMDB ID: 85285
PDB Deposition Date: 2010/5/26
Updated in MMDB: 2010/11
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Similar Structures:
Biological Unit for 2XFQ: dimeric; determined by author and by software (PISA)
Molecular Components in 2XFQ
Label Count Molecule
Proteins (2 molecules)
2
Amine Oxidase [flavin-containing] B(Gene symbol: MAOB)
Molecule annotation
Chemicals (7 molecules)
1
2
2
2
3
2
4
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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