(A*STAR Programme) Structure-based ligand discovery for overcoming multi-drug resistance.

ABCB1 – P-glycoprotein is an ATP-binding cassette (ABC) transporter. ABCB1 – along with a few other ABC proteins, is responsible for cancer chemotherapy failure in a high proportion of cases. It is able to transport xenobiotics and drugs out of cells – rendering them resistant to said compounds. At the blood-brain barrier, ABCB1 performs a vital role in maintaining the integrity of the brain. It performs a similar gatekeeper role in stem cells. The structure of ABCB1 has been studied for several years in the Ford laboratory, with 2 people in his group currently working on this. Good inhibitors or activators of ABCB1 are actively being sought. The Ford lab published the first structure of ABCB1 and has produced the only structure for the outward-facing conformation of the protein (ie with ATP bound). This project will combine the strengths in protein chemistry and structural biology of the Ford lab with the strengths in protein structure modelling, structure-based ligand discovery, and molecular dynamics simulation of biomolecules in the Fan laboratory at the BII, A*STAR in Singapore. In Manchester, the student will participate in the generation structural data for ABCB1 which is currently being expressed and purified in the Ford lab. The student will specifically carry out crystal trials and cryo-EM studies with known ABCB1 substrates and inhibitors with the aim of identifying likely binding sites. The work will then extend to protein structure modelling and structure-based ligand discovery. The candidate ligands from these efforts will be tested in a biochemical assay based on the purified protein.