Poster Presentation The 44th Lorne Conference on Protein Structure and Function 2019

Exploring the binding sites of human ATP- Binding Cassette B5 transporter by molecular docking (#123)

Lokeswari Prathyusha Tangella 1 2 , Elin S Gray 1 , Mahreen Arooj 2 3
  1. School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia
  2. School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA, Australia
  3. Department of Chemistry, University of Sharjah, Sharjah, United Arab Emirates

 

ATP-Binding Cassette (ABC) transporters are membrane proteins that mediate multidrug resistance (MDR) for anti-cancer drugs by the effluxion of anti-cancer drug from tumour cells, leading to decreased intracellular drug accumulation within tumour cells. ATP- Binding Cassette B5 (ABCB5) transporter is a member of the ABC family, and was reported to be overexpressed in melanoma, colorectal cancer, breast cancer, merkel cell carcinoma and leukaemia. This overexpression in ABCB5 transporter was reported to mediate MDR for chemotherapeutic drugs such as Doxorubicin, Carboplatin, and Rhodamine123 (fluorescent probe). ABCB5 is also suggested a stem marker and a prognostic marker for metastasis. However, the crystal structure of ABCB5 is not available to date, thus very little is known about the binding sites of this transporter. In this study, the binding sites for Rhodamine123, Doxorubicin and Carboplatin were predicted using molecular docking. Homology models of ABCB5 human transporter (812 amino acids) were generated using I-TASSER (threading approach) and SWISS-MODEL using ABCB1 mouse crystal structure as the template. Multisequence alignment of ABCB1 mouse and ABCB5 human by ClustalO showed a 57% sequence identity, between the two sequences. ABCB5 models were unique with six transmembrane helices and two nucleotide binding sites, unlike the other full and half transporters. The final model was selected based on SWISS-MODEL structural assessment tools, ERRAT and PROCHECK results and molecular docking was performed on this model. The binding sites predicted by molecular docking could be used to identify molecules that can competively block the effluxion of anti-cancer from tumour cells, thereby help in maintaining the therapeutic drug concentration within tumour cells and overcoming MDR.