Multidrug transporters: recent insights from cryo-electron microscopy-derived atomic structures and animal models.

Sabrina Lusvarghi,Suresh V Ambudkar,Michael M Gottesman,Robert W Robey

doi:10.12688/f1000research.21295.1

Sabrina Lusvarghi, Suresh V Ambudkar + Show 2 more

Open Access

https://doi.org/10.12688/f1000research.21295.1

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Abstract

P-glycoprotein, ABCG2, and MRP1 are members of the ATP-binding cassette (ABC) transporter superfamily that utilize energy from ATP-binding and hydrolysis to efflux a broad range of chemically dissimilar substrates including anticancer drugs. As a consequence, they play an important role in the pharmacokinetics and bioavailability of many drugs; in particular, their role in multidrug resistance in cancer cells as well as at the blood–brain barrier has been the subject of studies for decades. However, the atomic structures of these transporters in the presence of substrates or modulators and at different stages of the ATP-hydrolysis cycle have only recently been resolved by using cryo-electron microscopy. In addition, new animal models have shed new light on our understanding of the role of these transporters at the blood–brain barrier. This new information should open doors for the design of novel chemotherapeutics and treatments to bypass recognition by ABC drug pumps to overcome clinical drug resistance. In this review, we discuss the most recent advances in our understanding of ligand interactions and mechanistic aspects of drug transport based on atomic structures of these transporters as well as the development of new in vivo models to study their role in clinical drug resistance in cancer.

Highlights

Multidrug resistance (MDR)—resistance to multiple, structurally unrelated compounds—frequently arises during the treatment of cancer with chemotherapeutic agents
Increased efflux of chemotherapy drugs usually occurs via increased expression of ATP-binding cassette (ABC) transporters, membrane transporters that use energy derived from ATP hydrolysis to efflux drugs from the cell against a concentration gradient
There are three main ABC transporters that contribute to MDR, and all were discovered via drug-resistant cell lines developed by incubating cancer cell lines with increasing concentrations of chemotherapy drugs

Summary

Introduction

Multidrug resistance (MDR)—resistance to multiple, structurally unrelated compounds—frequently arises during the treatment of cancer with chemotherapeutic agents. The structure of MRP1 in the presence of ATP in the closed conformation reveals that LTC4 is effluxed out of the protein prior to ATP hydrolysis[24] It reveals movement of amino acids in the transmembrane region that forces the substrate out of the binding site by weakening the binding interaction and increasing steric hindrance[23]. Cryo-EM structures of P-gp and ABCG2 have identified ordered cholesterol and phospholipid molecules directly interacting with the transmembrane region[20,22], suggesting that the lipids in the membrane could modulate the conformational changes associated with binding of substrates and inhibitors. The power of using zebrafish as a model to study transporter inhibitors or to examine the ability of therapies to cross the BBB is an exciting possibility

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