ArticleThe Journal of biological chemistry2013
Mutations in intracellular loops 1 and 3 lead to misfolding of human P-glycoprotein (ABCB1) that can be rescued by cyclosporine A, which reduces its association with chaperone Hsp70.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Breaking the Efflux Barrier: P-Glycoprotein and Emerging Strategies to Overcome Multidrug Resistance in Cancer.Cancers · 2026Review
- (N)-Methanocarba Adenosine Derivatives as Dual Modulators of P-Glycoprotein and ABCG2 Transporters.Journal of medicinal chemistry · 2026Article
- Second-site suppressor mutations reveal connection between the drug-binding pocket and nucleotide-binding domain 1 of human P-glycoprotein (ABCB1).Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2023Article
- Theoretical insights on helix repacking as the origin of P-glycoprotein promiscuity.Scientific reports · 2020Article
- Replacing the eleven native tryptophans by directed evolution produces an active P-glycoprotein with site-specific, non-conservative substitutions.Scientific reports · 2020Article
- Evidence for the Interaction of AMolecular pharmacology · 2019Article
- Article
- Mapping discontinuous epitopes for MRK-16, UIC2 and 4E3 antibodies to extracellular loops 1 and 4 of human P-glycoprotein.Scientific reports · 2018Article
- Global alteration of the drug-binding pocket of human P-glycoprotein (ABCB1) by substitution of fifteen conserved residues reveals a negative correlation between substrate size and transport efficiency.Biochemical pharmacology · 2017Article
- Structures of the Multidrug Transporter P-glycoprotein Reveal Asymmetric ATP Binding and the Mechanism of Polyspecificity.The Journal of biological chemistry · 2017Article
- Human-Mouse Chimeras with Normal Expression and Function Reveal That Major Domain Swapping Is Tolerated by P-Glycoprotein (ABCB1).Biochemistry · 2016Article
- Drug-protein hydrogen bonds govern the inhibition of the ATP hydrolysis of the multidrug transporter P-glycoprotein.Biochemical pharmacology · 2016Article
- Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL.Experimental cell research · 2015Article
- The Transmission Interfaces Contribute Asymmetrically to the Assembly and Activity of Human P-glycoprotein.The Journal of biological chemistry · 2015Article
- Mutational Analysis of Intracellular Loops Identify Cross Talk with Nucleotide Binding Domains of Yeast ABC Transporter Cdr1p.Scientific reports · 2015Article
- Locking intracellular helices 2 and 3 together inactivates human P-glycoprotein.The Journal of biological chemistry · 2014Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
P-glycoprotein (P-gp) is an ATP binding cassette transporter that effluxes a variety of structurally diverse compounds including anticancer drugs. Computational models of human P-gp in the apo- and nucleotide-bound conformation show that the adenine group of ATP forms hydrogen bonds with the conserved Asp-164 and Asp-805 in intracellular loops 1 and 3, respectively, which are located at the interface between the nucleotide binding domains and transmembrane domains. We investigated the role of Asp-164 and Asp-805 residues by substituting them with cysteine in a cysteine-less background. It was observed that the D164C/D805C mutant, when expressed in HeLa cells, led to misprocessing of P-gp, which thus failed to transport the drug substrates. The misfolded protein could be rescued to the cell surface by growing the cells at a lower temperature (27 °C) or by treatment with substrates (cyclosporine A, FK506), modulators (tariquidar), or small corrector molecules. We also show that short term (4-6 h) treatment with 15 μM cyclosporine A or FK506 rescues the pre-formed immature protein trapped in the endoplasmic reticulum in an immunophilin-independent pathway. The intracellularly trapped misprocessed protein associates more with chaperone Hsp70, and the treatment with cyclosporine A reduces the association of mutant P-gp, thus allowing it to be trafficked to the cell surface. The function of rescued cell surface mutant P-gp is similar to that of wild-type protein. These data demonstrate that the Asp-164 and Asp-805 residues are not important for ATP binding, as proposed earlier, but are critical for proper folding and maturation of a functional transporter.
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