Abstract
P-glycoprotein (P-gp or ABCB1) is a member of the broad family of ABC transporters. P-gp participates in the establishment of physiological barriers limiting cellular access of a large number of toxic compounds. It thus plays important roles in the pharmacokinetics of these compounds. Cancer cells and cells infected by viruses exploit the presence of P-gp to fend off drug treatment, rendering them multidrug-resistant. Overcoming multidrug resistance caused by expression of ABC transporters has gained increasing attention in the field of drug development. Recently, studies of P-gp, especially from structural investigations by both cryo-electron microscopy and X-ray crystallography, have provided high-resolution mechanistic details for the function of this transporter. Structures with increasing resolution and accuracy in various substrate- and inhibitor-bound forms are available for analysis and a consensus on the mechanism of substrate polyspecificity is emerging. The use of new structural information may aid development of P-gp inhibitors as well as compounds that may bypass P-gp action.
Highlights
Multidrug resistance (MDR), the simultaneous development of cellular resistance to multiple anticancer drugs, remains a major obstacle in effective treatment of cancer by chemotherapy[1]
Multiple mechanisms are known in MDR development, one well-studied mechanism is the overexpression of ATP-dependent efflux pumps, represented by ABC transporters such as P-glycoprotein (P-gp or ABCB1)
We review recent efforts in the field to understand, both biochemically and structurally, the mechanism of function of mammalian P-glycoprotein, focusing on the mechanism of substrate specificity
Summary
Multidrug resistance (MDR), the simultaneous development of cellular resistance to multiple anticancer drugs, remains a major obstacle in effective treatment of cancer by chemotherapy[1]. In an attempt to obtain higher resolution structures in an outward-open conformation, Esser and colleagues created a mP-gp mutant (lnkmP-gp) with a linker shortened by 34 residues.
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