3VH9

Crystal structure of Aeromonas proteolytica aminopeptidase complexed with 8-quinolinol

Summary for 3VH9

• Entry DOI: 10.2210/pdb3vh9/pdb
• Related: 1AMP 1CP6 1FT7 1IGB 1LOK 1RTQ 1TXR 1XRY 2ANP 2DEA 2IQ6 2NYQ 2PRQ 3B35 3B3C 3B3S 3B3T 3B3V 3B3W 3B7I 3FH4
• Descriptor: Bacterial leucyl aminopeptidase, ZINC ION, quinolin-8-ol, ... (8 entities in total)
• Functional Keywords: 8-quinolinol, dinuclear zinc hydrolases, aminopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Vibrio proteolyticus
• Cellular location: Secreted: Q01693
• Total number of polymer chains: 1
• Total formula weight: 33248.37

Authors

Saijo, S.,Hanaya, K.,Suetsugu, M.,Kobayashi, K.,Yamato, I.,Aoki, S. (deposition date: 2011-08-24, release date: 2012-05-02, Last modification date: 2024-11-13)

Primary citation

Hanaya, K.,Suetsugu, M.,Saijo, S.,Yamato, I.,Aoki, S.
Potent inhibition of dinuclear zinc(II) peptidase, an aminopeptidase from Aeromonas proteolytica, by 8-quinolinol derivatives: inhibitor design based on Zn(2+) fluorophores, kinetic, and X-ray crystallographic study.
J.Biol.Inorg.Chem., 17:517-529, 2012

PubMed Abstract: The selective inhibition of an aminopeptidase from Aeromonas proteolytica (AAP), a dinuclear Zn(2+) hydrolase, by 8-quinolinol (8-hydroxyquinoline, 8-HQ) derivatives is reported. We previously reported on the preparation of 8-HQ-pendant cyclens as Zn(2+) fluorophores (cyclen is 1,4,7,10-tetraazacyclododecane), in which the nitrogen and phenolate of the 8-HQ units (as well as the four nitrogens of cyclen) bind to Zn(2+) in a bidentate manner to form very stable Zn(2+) complexes at neutral pH (K (d) = 8-50 fM at pH 7.4). On the basis of this finding, it was hypothesized that 8-HQ derivatives have the potential to function as specific inhibitors of Zn(2+) enzymes, especially dinuclear Zn(2+) hydrolases. Assays of 8-HQ derivatives as inhibitors were performed against commercially available dinuclear Zn(2+) enzymes such as AAP and alkaline phosphatase. 8-HQ and the 5-substituted 8-HQ derivatives were found to be competitive inhibitors of AAP with inhibition constants of 0.16-29 μM at pH 8.0. The nitrogen at the 1-position and the hydroxide at the 8-position of 8-HQ were found to be essential for the inhibition of AAP. Fluorescence titrations of these drugs with AAP and an X-ray crystal structure analysis of an AAP-8-HQ complex (1.3-Å resolution) confirmed that 8-HQ binds to AAP in the "Pyr-out" mode, in which the hydroxide anion of 8-HQ bridges two Zn(2+) ions (Zn1 and Zn2) in the active site of AAP and the nitrogen atom of 8-HQ coordinates to Zn1 (Protein Data Bank code 3VH9).

PubMed: 22311113
DOI: 10.1007/s00775-012-0873-4

Experimental method

X-RAY DIFFRACTION (1.29 Å)