ArticleThe Journal of biological chemistry2014
Locking intracellular helices 2 and 3 together inactivates human P-glycoprotein.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 21 citations in OpenAlex.
- Mechanistic insights into P-glycoprotein ligand transport and inhibition revealed by enhanced molecular dynamics simulations.Computational and structural biotechnology journal · 2024Article
- Probing the Allosteric Modulation of P-Glycoprotein: A Medicinal Chemistry Approach Toward the Identification of Noncompetitive P-Gp Inhibitors.ACS omega · 2023Article
- Computational Insights into Allosteric Conformational Modulation of P-Glycoprotein by Substrate and Inhibitor Binding.Molecules (Basel, Switzerland) · 2020Article
- Theoretical insights on helix repacking as the origin of P-glycoprotein promiscuity.Scientific reports · 2020Article
- Conformational dynamics of P-glycoprotein in lipid nanodiscs and detergent micelles reveal complex motions on a wide time scale.The Journal of biological chemistry · 2018Article
- Mapping the Binding Site of the Inhibitor Tariquidar That Stabilizes the First Transmembrane Domain of P-glycoprotein.The Journal of biological chemistry · 2015Article
- The Transmission Interfaces Contribute Asymmetrically to the Assembly and Activity of Human P-glycoprotein.The Journal of biological chemistry · 2015Article
- Cysteines introduced into extracellular loops 1 and 4 of human P-glycoprotein that are close only in the open conformation spontaneously form a disulfide bond that inhibits drug efflux and ATPase activity.The Journal of biological chemistry · 2014Article
- Identification of the distance between the homologous halves of P-glycoprotein that triggers the high/low ATPase activity switch.The Journal of biological chemistry · 2014Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The P-glycoprotein (P-gp) drug pump (ABCB1) has two transmembrane domains and two nucleotide-binding domains (NBDs). Coupling of the drug-binding sites in the transmembrane domains to the NBDs occurs through interaction of the intracellular helices (IHs) with residues in the NBDs (IH1/IH4/NBD1 and IH2/IH3/NBD2). We showed previously that cross-linking of cysteines in IH3 and IH1 with a short cross-linker mimicked drug binding as it activated P-gp ATPase activity. Here we show that residue A259C(IH2) could be directly cross-linked to W803C(IH3). Cross-linking was inhibited by the presence of ATP and adenosine 5'-(β,γ-imino)triphosphate but not by ADP. Cross-linking of mutant A259C/W803C inhibited its verapamil-stimulated ATPase activity mutant, but activity was restored after addition of dithiothreitol. Because these residues are close to the ball-and-socket joint A266C(IH2)/Phe(1086)(NBD2), we mutated the adjacent Tyr(1087)(NBD2) close to IH3. Mutants Y1087A and Y1087L, but not Y1087F, were misprocessed, and all inhibited ATPase activity. Mutation of hydrophobic residues (F793A, L797A, L814A, and L818A) flanking IH3 also inhibited maturation. The results suggest that these residues, together with Trp(803) and Phe(804), form a large hydrophobic pocket. The results show that there is an important hydrophobic network at the IH2/IH3/NBD2 transmission interface that is critical for folding and activity of P-gp.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.