Journal article

Identification of modulating residues defining the catalytic cleft of insulin-regulated aminopeptidase

Siying Ye, Siew Yeen Chai, Rebecca A Lew, David B Ascher, Craig J Morton, Michael W Parker, Anthony L Albiston

BIOCHEMISTRY AND CELL BIOLOGY | CANADIAN SCIENCE PUBLISHING | Published : 2008

Abstract

Inhibition of insulin-regulated aminopeptidase (IRAP) has been demonstrated to facilitate memory in rodents, making IRAP a potential target for the development of cognitive enhancing therapies. In this study, we generated a 3-D model of the catalytic domain of IRAP based on the crystal structure of leukotriene A4 hydrolase (LTA4H). This model identified two key residues at the 'entrance' of the catalytic cleft of IRAP, Ala427 and Leu483, which present a more open arrangement of the S1 subsite compared with LTA4H. These residues may define the size and 3-D structure of the catalytic pocket, thereby conferring substrate and inhibitor specificity. Alteration of the S1 subsite by the mutation A4..

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