Human kinesin Eg5 plays an essential role in mitosis by separating duplicated centrosomes and establishing the bipolar spindle. Eg5 is an interesting drug target for the development of cancer chemotherapy, with seven inhibitors already in clinical trials. In the present paper, we report the crystal structure of the Eg5 motor domain complexed with a potent antimitotic inhibitor STLC (S-trityl-L-cysteine) to 2.0 Å (1 Å=0.1 nm) resolution. The Eg5–STLC complex crystallizes in space group P32 with three molecules per asymmetric unit. Two of the molecules reveal the final inhibitor-bound state of Eg5, whereby loop L5 has swung downwards to close the inhibitor-binding pocket, helix α4 has rotated by approx. 15 ° and the neck-linker has adopted a docked conformation. The third molecule, however, revealed an unprecedented intermediate state, whereby local changes at the inhibitor-binding pocket have not propagated to structural changes at the switch II cluster and neck-linker. This provides structural evidence for the sequence of drug-induced conformational changes.

Drug resistance is a serious concern in a clinical setting jeopardizing treatment for both infectious agents and cancers alike. The wide-spread emergence of multi-drug resistant (MDR) phenotypes from bacteria to cancerous cells necessitates the need to target resistance mechanisms and prevent the emergence of resistant mutants. Drug efflux seems to be one of the preferred approaches embraced by both microbial and mammalian cells alike, to thwart the action of chemotherapeutic agents thereby leading to a drug resistant phenotype. Relative to microbes, which predominantly employs proton motive force (PMF) powered, Major Facilitator Superfamily (MFS)/Resistance Nodulation and Division (RND) classes of efflux pumps to efflux drugs, cancerous cells preferentially use ATP fuelled ATP binding cassette (ABC) transporters to extrude chemotherapeutic agents. The prevalence, evolutionary characteristics and overlapping functions of ABC transporters have been highlighted in this review. Additionally, we outline the role of ABC pumps in conferring MDR phenotype to both bacteria and cancerous cells and underscore the importance of efflux pump inhibitors (EPI) to mitigate drug resistance. Based on the literature reports and analysis, we reason out feasibility of employing bacteria as a tool to screen for EPI’s targeting ABC pumps of cancerous cells.