Identification and characterisation of putative drug binding sites in human ATP-binding cassette B5 (ABCB5) transporter

Lokeswari P Tangella; Mahreen Arooj; Evelyne Deplazes; Elin S Gray; Ricardo L Mancera

doi:10.1016/j.csbj.2020.12.042

Identification and characterisation of putative drug binding sites in human ATP-binding cassette B5 (ABCB5) transporter

Comput Struct Biotechnol J. 2020 Dec 30:19:691-704. doi: 10.1016/j.csbj.2020.12.042. eCollection 2021.

Authors

Lokeswari P Tangella¹, Mahreen Arooj², Evelyne Deplazes^{3

4}, Elin S Gray¹, Ricardo L Mancera³

Affiliations

¹ School of Medical and Health Sciences, Edith Cowan University, Perth, WA 6027, Australia.
² Department of Chemistry, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates.
³ School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute and Curtin Institute for Computation, Curtin University, GPO Box U1987, Perth, WA 6845, Australia.
⁴ School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia.

Abstract

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.

Keywords: ABC transporter; Full-length ABCB5 transporter; Molecular docking; Molecular dynamics simulations; Molecular modelling.