You are not logged in.

Phenylalanine-544 plays a key role in substrate and inhibitor binding by providing a hydrophobic packing point at the active site of insulin-regulated aminopeptidase

Albiston, Anthony L., Pham, Vi, Ye, Siying, Ng, Leelee, Lew, Rebecca A., Thompson, Philip E., Holien, Jessica K., Morton, Craig J., Parker, Michael W. and Chai, Siew Yeen 2010, Phenylalanine-544 plays a key role in substrate and inhibitor binding by providing a hydrophobic packing point at the active site of insulin-regulated aminopeptidase, Molecular pharmacology, vol. 78, no. 4, pp. 600-607, doi: 10.1124/mol.110.065458.

Attached Files
Name Description MIMEType Size Downloads

Title Phenylalanine-544 plays a key role in substrate and inhibitor binding by providing a hydrophobic packing point at the active site of insulin-regulated aminopeptidase
Author(s) Albiston, Anthony L.
Pham, Vi
Ye, Siying
Ng, Leelee
Lew, Rebecca A.
Thompson, Philip E.
Holien, Jessica K.
Morton, Craig J.
Parker, Michael W.
Chai, Siew Yeen
Journal name Molecular pharmacology
Volume number 78
Issue number 4
Start page 600
End page 607
Total pages 8
Publisher American Society for Pharmacology and Experimental Therapeutics
Place of publication Bethesda, Md.
Publication date 2010-10
ISSN 0026-895X
1521-0111
Summary Inhibitors of insulin-regulated aminopeptidase (IRAP) improve memory and are being developed as a novel treatment for memory loss. In this study, the binding of a class of these inhibitors to human IRAP was investigated using molecular docking and site-directed mutagenesis. Four benzopyran-based IRAP inhibitors with different affinities were docked into a homology model of the catalytic site of IRAP. Two 4-pyridinyl derivatives orient with the benzopyran oxygen interacting with the Zn2+ ion and a direct parallel ring-stack interaction between the benzopyran rings and Phe544. In contrast, the two 4-quinolinyl derivatives orient in a different manner, interacting with the Zn2+ ion via the quinoline nitrogen, and Phe544 contributes an edge-face hydrophobic stacking point with the benzopyran moiety. Mutagenic replacement of Phe544 with alanine, isoleucine, or valine resulted in either complete loss of catalytic activity or altered hydrolysis velocity that was substrate-dependent. Phe544 is also important for inhibitor binding, because these mutations altered the Ki in some cases, and docking of the inhibitors into the corresponding Phe544 mutant models revealed how the interaction might be disturbed. These findings demonstrate a key role of Phe544 in the binding of the benzopyran IRAP inhibitors and for optimal positioning of enzyme substrates during catalysis.
Notes Article first published online 13th July, 2010
Language eng
DOI 10.1124/mol.110.065458
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2010, The American Society for Pharmacology and Experimental Therapeutics
Persistent URL http://hdl.handle.net/10536/DRO/DU:30040946

Document type: Journal Article
Collection: School of Medicine
Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 11 times in TR Web of Science
Scopus Citation Count Cited 13 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 173 Abstract Views, 2 File Downloads  -  Detailed Statistics
Created: Wed, 07 Dec 2011, 10:04:56 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.