Structure of the human mitochondrial monoamine oxidase B: New chemical implications for neuroprotectant drug design

C. Binda, F. Hubálek, M. Li, N. Castagnoli, D. E. Edmondson, A. Mattevi

Research output: Contribution to journalArticlepeer-review

Abstract

Monoamine oxidase B (MAO-B) is an outer mitochondrial membrane-bound flavoenzyme that is a well-known target for antidepressant and neuroprotective drugs. The 3Å resolution structure of recombinant human MAO-B originally determined was of the enzyme complexed with pargyline, an irreversible inhibitor covalently bound to the N5 atom of the flavin coenzyme. The crystal structure shows that the enzyme is dimeric. Each monomer binds to the membrane via a C-terminal transmembrane helix and by apolar loops located at various positions in the sequence. Substrate binding to the enzyme involves negotiating a loop covering a 290Å entrance apolar cavity before reaching an apolar 420Å substrate cavity where the flavin coenzyme is located. The 1.7Å isatin-MAO-B structure allowed a detailed examination of the enzyme's active site. A novel specific reversible MAO-B inhibitor, which is found as a contaminant in polystyrene plastics (1,4-diphenyl-2-butene), binds in both the entrance and the substrate cavity. Analogous MAO-B-specific inhibitors that bind in a manner traversing both cavities include trans-trans farnesol and chlorostyrylcaffeine. The rotation of the Ile199 side chain to an "open" conformation plays an essential role in this specificity. These results form a molecular basis for the design of new human MAO-B-specific reversible inhibitors.

Original languageEnglish (US)
Pages (from-to)S5-S7
JournalNeurology
Volume67
Issue number7 SUPPL. 2
DOIs
StatePublished - Oct 2006

ASJC Scopus subject areas

  • Clinical Neurology

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