Active participation of membrane lipids in inhibition of multidrug transporter P-glycoprotein

Kapoor, Karan; Pant, Shashank; Tajkhorshid, Emad

doi:10.1039/d0sc06288j

Cited by 24 publications

(36 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 32 , 45 , 46 A recent MD study also demonstrates a broader range of distances between the NBDs and TMDs and increased lipid access events in the presence of the inhibitor tariquidar. 28 Our results for zosuquidar in the post-hydrolysis state are consistent with these findings. Zosuquidar in the post-hydrolysis state decreases protection for TMH9 and neighboring ICH3, as well as ICH4 and neighboring TMHs 10 and 11.…”

Section: Discussionsupporting

confidence: 90%

Long Range Communication between the Drug-Binding Sites and Nucleotide Binding Domains of the Efflux Transporter ABCB1

Clouser

Atkins

2022

Biochemistry

View full text Add to dashboard Cite

The ABC efflux pump P-glycoprotein (P-gp) transports a wide variety of drugs and is inhibited by others. Some drugs stimulate ATP hydrolysis at the nucleotide binding domains (NBDs) and are transported, others uncouple ATP hydrolysis and transport, and others inhibit ATP hydrolysis. The molecular basis for the different behavior of these drugs is not well understood despite the availability of several structural models of P-gp complexes with ligands bound. Hypothetically, ligands differentially alter the conformational dynamics of peptide segments that mediate the coupling between the drug binding sites and the NBDs. Here, we explore by hydrogen-deuterium exchange mass spectrometry the dynamic consequences of a classic substrate and inhibitor, vinblastine and zosuquidar, binding to mouse P-gp (mdr1a) in lipid nanodiscs. The dynamics of P-gp in nucleotide-free, pre-hydrolysis, and post-hydrolysis states in the presence of each drug reveal distinct mechanisms of ATPase stimulation and implications for transport. For both drugs, there are common regions affected in a similar manner, suggesting that particular networks are the key to stimulating ATP hydrolysis. However, drug binding effects diverge in the post-hydrolysis state, particularly in the intracellular helices (ICHs 3 and 4) and neighboring transmembrane helices. The local dynamics and conformational equilibria in this region are critical for the coupling of drug binding and ATP hydrolysis and are differentially modulated in the catalytic cycle.

show abstract

Section: Discussionsupporting

confidence: 90%

Long Range Communication between the Drug-Binding Sites and Nucleotide Binding Domains of the Efflux Transporter ABCB1

Clouser

Atkins

2022

Biochemistry

View full text Add to dashboard Cite

show abstract

“…Alternatively, as suggested by a recent MD study, the stable binding of a third-generation inhibitor (tariquidar in this case) inside the DBP may promote increased lipid diffusion inside the lumen, locking Pgp in a catalytically inactive open IF-like state. 94 This may further enhance the inhibitory function of these molecules.…”

Section: Discussionmentioning

confidence: 99%

Extended-ensemble docking to probe dynamic variation of ligand binding sites during large-scale structural changes of proteins

2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…to play an important role in MDR and ABC transporters (Kapoor et al, 2021;Marcoux et al, 2013;Zoghbi et al, 2017). Lipid rafts are cholesterol-and sphingolipid-enriched microdomains on the plasma membrane, which provide a platform for biological processes (Sezgin et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Targeted disruption of mitochondria potently reverses multidrug resistance in cancer therapy

Liu

Rong

Chen

et al. 2022

British J Pharmacology

View full text Add to dashboard Cite

Background and purpose Multidrug resistance (MDR) is a major obstacle to the successful treatment of cancer. Ample evidence shows that ATP‐binding cassette (ABC) transporters and high‐energy states in cells are linked to cancer drug resistance. Our previous work reported an engineered therapeutic protein named PAK, which selectively inhibited tumour progression by targeting mitochondria. Experimental approach We studied the effects of PAK on reversing drug resistance in MDR phenotypic cells and xenograft mouse models. Effects of PAK on the process of mitochondrial energy production, ABC transporter expression, and drugs enrichment were investigated in cancer cells. RNA‐seq and co‐immunoprecipitation were employed to analyse the mechanism of PAK on the redistribution of ABC transporters. Key results PAK promoted the enrichment of drugs in MDR cancer cells, thus enhancing the sensitivity of cancer cells to chemotherapy. Furthermore, PAK was colocalized in the mitochondria and initiated mitochondrial injury by selectively inhibiting the mitochondrial complex V. Also, ABCB1 and ABCC1 were redistributed from the plasma membrane to the cytoplasm through the disruption of lipid rafts, which was attributed to the low energy state and decreased cholesterol levels. Conclusions and implications Our results revealed a previously unrecognized pattern of reversal of drug resistance and have suggested mitochondria as a clinically relevant target for the treatment of MDR malignant tumours.

show abstract

Active participation of membrane lipids in inhibition of multidrug transporter P-glycoprotein

Abstract: P-glycoprotein (Pgp) is a major efflux pump in humans, overexpressed in a variety of cancers and associated with the development of multi-drug resistance. Allosteric modulation by various ligands (e.g., transport...

Cited by 24 publications

References 68 publications

Long Range Communication between the Drug-Binding Sites and Nucleotide Binding Domains of the Efflux Transporter ABCB1

Long Range Communication between the Drug-Binding Sites and Nucleotide Binding Domains of the Efflux Transporter ABCB1

Extended-ensemble docking to probe dynamic variation of ligand binding sites during large-scale structural changes of proteins

Targeted disruption of mitochondria potently reverses multidrug resistance in cancer therapy

Contact Info

Product

Resources

About