3ZYX

Crystal structure of human monoamine oxidase B in complex with methylene blue and bearing the double mutation I199A-Y326A

Summary for 3ZYX

• Entry DOI: 10.2210/pdb3zyx/pdb
• Related: 1GOS 1H8R 1OJ9 1OJA 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 2XFQ 2XFU
• Descriptor: AMINE OXIDASE [FLAVIN-CONTAINING] B, FLAVIN-ADENINE DINUCLEOTIDE, 3,7-BIS(DIMETHYLAMINO)PHENOTHIAZIN-5-IUM, ... (4 entities in total)
• Functional Keywords: oxidoreductase, inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Mitochondrion outer membrane; Single-pass type IV membrane protein; Cytoplasmic side: P27338
• Total number of polymer chains: 2
• Total formula weight: 119284.62

Authors

Milczek, E.M.,Binda, C.,Rovida, S.,Mattevi, A.,Edmondson, D.E. (deposition date: 2011-08-29, release date: 2011-12-14, Last modification date: 2024-10-09)

Primary citation

Milczek, E.M.,Binda, C.,Rovida, S.,Mattevi, A.,Edmondson, D.E.
The 'Gating' Residues Ile199 and Tyr326 in Human Monoamine Oxidase B Function in Substrate and Inhibitor Recognition.
FEBS J., 278:4860-, 2011

PubMed Abstract: The major structural difference between human monoamine oxidases A (MAO A) and B (MAO B) is that MAO A has a monopartite substrate cavity of ~550 Å(3) volume and MAO B contains a dipartite cavity structure with volumes of ~290 Å(3) (entrance cavity) and ~400 Å(3) (substrate cavity). Ile199 and Tyr326 side chains separate these two cavities in MAO B. To probe the function of these gating residues, Ile199Ala and Ile199Ala-Tyr326Ala mutant forms of MAO B were investigated. Structural data on the Ile199Ala MAO B mutant show no alterations in active site geometries compared with wild-type enzyme while the Ile199Ala-Tyr326Ala MAO B mutant exhibits alterations in residues 100-103 which are part of the loop gating the entrance to the active site. Both mutant enzymes exhibit catalytic properties with increased amine K(M) but unaltered k(cat) values. The altered K(M) values on mutation are attributed to the influence of the cavity structure in the binding and subsequent deprotonation of the amine substrate. Both mutant enzymes exhibit weaker binding affinities relative to wild-type enzyme for small reversible inhibitors. Ile199Ala MAO B exhibits an increase in binding affinity for reversible MAO B specific inhibitors which bridge both cavities. The Ile199Ala-Tyr326Ala double mutant exhibits inhibitor binding properties more similar to those of MAO A than to MAO B. These results demonstrate that the bipartite cavity structure in MAO B plays an important role in substrate and inhibitor recognition to distinguish its specificities from those of MAO A and provide insights into specific reversible inhibitor design for these membrane-bound enzymes.

PubMed: 21978362
DOI: 10.1111/J.1742-4658.2011.08386.X

Experimental method

X-RAY DIFFRACTION (2.2 Å)