1H81

STRUCTURE OF POLYAMINE OXIDASE IN THE REDUCED STATE

Summary for 1H81

• Entry DOI: 10.2210/pdb1h81/pdb
• Related: 1B37 1B5Q 1H82 1H83 1H84 1H86
• Descriptor: POLYAMINE OXIDASE, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-D-fucopyranose-(1-3)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: flavin-dependent amine oxidase, oxidoreductase
• Biological source: ZEA MAYS (MAIZE)
• Total number of polymer chains: 3
• Total formula weight: 165195.65

Authors

Binda, C.,Coda, A.,Angelini, R.,Federico, R.,Ascenzi, P.,Mattevi, A. (deposition date: 2001-01-24, release date: 2001-01-31, Last modification date: 2023-12-13)

Primary citation

Binda, C.,Angelini, R.,Federico, R.,Ascenzi, P.,Mattevi, A.
Structural Bases for Inhibitor Binding and Catalysis in Polyamine Oxidase
Biochemistry, 40:2766-, 2001

PubMed Abstract: Polyamine oxidase (PAO) carries out the FAD-dependent oxidation of the secondary amino groups of spermidine and spermine, a key reaction in the polyamine catabolism. The active site of PAO consists of a 30 A long U-shaped catalytic tunnel, whose innermost part is located in front of the flavin ring. To provide insight into the PAO substrate specificity and amine oxidation mechanism, we have investigated the crystal structure of maize PAO in the reduced state and in complex with three different inhibitors, guazatine, 1,8-diaminooctane, and N(1)-ethyl-N(11)-[(cycloheptyl)methyl]-4,8-diazaundecane (CHENSpm). In the reduced state, the conformation of the isoalloxazine ring and the surrounding residues is identical to that of the oxidized enzyme. Only Lys300 moves away from the flavin to compensate for the change in cofactor protonation occurring upon reduction. The structure of the PAO.inhibitor complexes reveals an exact match between the inhibitors and the PAO catalytic tunnel. Inhibitor binding does not involve any protein conformational change. Such lock-and-key binding occurs also in the complex with CHENSpm, which forms a covalent adduct with the flavin N5 atom. Comparison of the enzyme complexes hints at an "out-of-register" mechanism of inhibition, in which the inhibitor secondary amino groups are not properly aligned with respect to the flavin to allow oxidation. Except for the Glu62-Glu170 pair, no negatively charged residues are involved in the recognition of substrate and inhibitor amino groups, which is in contrast to other polyamine binding proteins. This feature may be exploited in the design of drugs specifically targeting PAO.

PubMed: 11258887
DOI: 10.1021/BI002751J

Experimental method

X-RAY DIFFRACTION (2.1 Å)