Document Type
Journal Article
Publication Title
Computational and Structural Biotechnology Journal
Volume
19
First Page
691
Last Page
704
Publisher
Elsevier
School
School of Medical and Health Sciences
RAS ID
32734
Funders
Edith Cowan University Curtin University UTS Chancellor's Postdoctoral Research Fellowship Australian Government Government of Western Australia
Abstract
© 2020 The Author(s) The human ATP-binding cassette B5 (ABCB5) transporter, a member of the ABC transporter superfamily, is linked to chemoresistance in tumour cells by drug effluxion. However, little is known about its structure and drug-binding sites. In this study, we generated an atomistic model of the full-length human ABCB5 transporter with the highest quality using the X-ray crystal structure of mouse ABCB1 (Pgp1), a close homologue of ABCB5 and a well-studied member of the ABC family. Molecular dynamics simulations were used to validate the atomistic model of ABCB5 and characterise its structural properties in model cell membranes. Molecular docking simulations of known ABCB5 substrates such as taxanes, anthracyclines, camptothecin and etoposide were then used to identify at least three putative binding sites for chemotherapeutic drugs transported by ABCB5. The location of these three binding sites is predicted to overlap with the corresponding binding sites in Pgp1. These findings will serve as the basis for future in vitro studies to validate the nature of the identified substrate-binding sites in the full-length ABCB5 transporter.
DOI
10.1016/j.csbj.2020.12.042
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Comments
Tangella, L. P., Arooj, M., Deplazes, E., Gray, E. S., & Mancera, R. L. (2021). Identification and characterisation of putative drug binding sites in human ATP-binding cassette B5 (ABCB5) transporter. Computational and Structural Biotechnology Journal, 19, 691-704. https://doi.org/10.1016/j.csbj.2020.12.042