High resolution crystal structures of human kynurenine aminotransferase‐I bound to PLP cofactor, and in complex with aminooxyacetate

Naveed A. Nadvi; Noeris K. Salam; Joohong Park; Fady N. Akladios; Vimal Kapoor; Charles A. Collyer; Mark D. Gorrell; William Bret Church

doi:10.1002/pro.3119

journal article Mar 06, 2017

High resolution crystal structures of human kynurenine aminotransferase‐I bound to PLP cofactor, and in complex with aminooxyacetate

Naveed A. Nadvi Noeris K. Salam Joohong Park Fady N. Akladios Vimal Kapoor Charles A. Collyer Mark D. Gorrell

William Bret Church

Protein Science Vol. 26 No. 4 pp. 727-736 · Wiley

View at Publisher Save 10.1002/pro.3119

Abstract

AbstractIn this study, we report two high‐resolution structures of the pyridoxal 5′ phosphate (PLP)‐dependent enzyme kynurenine aminotransferase‐I (KAT‐I). One is the native structure with the cofactor in the PLP form bound to Lys247 with the highest resolution yet available for KAT‐I at 1.28 Å resolution, and the other with the general PLP‐dependent aminotransferase inhibitor, aminooxyacetate (AOAA) covalently bound to the cofactor at 1.54 Å. Only small conformational differences are observed in the vicinity of the aldimine (oxime) linkage with which the PLP forms the Schiff base with Lys247 in the 1.28 Å resolution native structure, in comparison to other native PLP‐bound structures. We also report the inhibition of KAT‐1 by AOAA and aminooxy‐phenylpropionic acid (AOPP), with IC50s of 13.1 and 5.7 μM, respectively. The crystal structure of the enzyme in complex with the inhibitor AOAA revealed that the cofactor is the PLP form with the external aldimine linkage. The location of this oxime with the PLP, which forms in place of the native internal aldimine linkage of PLP of the native KAT‐I, is away from the position of the native internal aldimine, with the free Lys247 substantially retaining the orientation of the native structure. Tyr101, at the active site, was observed in two conformations in both structures.

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Details

Published: Mar 06, 2017
Vol/Issue: 26(4)
Pages: 727-736
License: View

Authors

N

Naveed A. Nadvi

Group in Biomolecular Structure and Informatics Faculty of Pharmacy, University of Sydney Sydney New South Wales Australia; Molecular Hepatology, Centenary Institute and Sydney Medical School, University of Sydney Sydney New South Wales Australia

N

Noeris K. Salam

Group in Biomolecular Structure and Informatics Faculty of Pharmacy, University of Sydney Sydney New South Wales Australia

J

Joohong Park

Molecular Hepatology, Centenary Institute and Sydney Medical School, University of Sydney Sydney New South Wales Australia

F

Fady N. Akladios

Group in Biomolecular Structure and Informatics Faculty of Pharmacy, University of Sydney Sydney New South Wales Australia

V

Vimal Kapoor

School of Medicine and Pharmacology The University of Western Australia Perth Western, Australia Australia

C

Charles A. Collyer

School of Molecular Bioscience University of Sydney Sydney New South Wales Australia

M

Mark D. Gorrell

Molecular Hepatology, Centenary Institute and Sydney Medical School, University of Sydney Sydney New South Wales Australia

W

William Bret Church

Group in Biomolecular Structure and Informatics Faculty of Pharmacy, University of Sydney Sydney New South Wales Australia

Funding

Rebecca L. Cooper Medical Research Foundation

Cite This Article

Naveed A. Nadvi, Noeris K. Salam, Joohong Park, et al. (2017). High resolution crystal structures of human kynurenine aminotransferase‐I bound to PLP cofactor, and in complex with aminooxyacetate. Protein Science, 26(4), 727-736. https://doi.org/10.1002/pro.3119

High resolution crystal structures of human kynurenine aminotransferase‐I bound to PLP cofactor, and in complex with aminooxyacetate

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