Human P-glycoprotein Contains a Greasy Ball-and-Socket Joint at the Second Transmission Interface

Loo, Tip W.; Bartlett, M. Claire; Clarke, David M.

doi:10.1074/jbc.m113.484550

Cited by 41 publications

(51 citation statements)

References 41 publications

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“…4). Although we showed previously that mutation of the adjacent Phe 1086 to Ala also inhibited activity (16), the activity of P-gp was much more sensitive to changes to Tyr 1087 . For example, mutation of Phe 1086 to Leu, Phe, or Trp yielded P-gps with activities similar to the wild-type protein.…”

mentioning

confidence: 64%

“…5A). These results show that maturation of P-gp was more sensitive to changes to Tyr 1087 compared with Phe 1086 because the F1086L mutation did not inhibit maturation (16).…”

Section: Mutating Aromatic Residues Trpmentioning

confidence: 80%

“…1B) along with F793A, L814A, and L818A (data not shown) also inhibited maturation so that the 150-kDa protein was the major product. 803 and Phe 804 in IH3 Inhibits Maturation but Not Activity-We showed previously that hydrophobic residues at the IH2-NBD2 interface were particularly important for maturation and activity of P-gp (16). Because W803A and F804A mutations in IH3 yielded the immature 150-kDa immature P-gp as the major product, we tested whether the mutants could be rescued with cyclosporine A.…”

Section: Mutations To Hydrophobic Residues In Ih3 and Flankingmentioning

confidence: 99%

“…It appears that TMD/NBD cross-talk is mediated by four intracellular loops (ICLs) in the TMDs. We showed recently that it is possible to mimic the effects of drug binding to activate ATPase activity by cross-linking ICL1(TMD1) in close proximity to ICL3(TMD2) (15,16).…”

mentioning

confidence: 99%

“…In this study, we tested our prediction that P-gp requires NBD2 because IH3-NBD2 interactions (predicted to involve Tyr 1087 in NBD2 (34)) are critical for maturation of P-gp during synthesis. In addition, we tested whether cross-linking of IH3 to IH2 would have the opposite effect of cross-linking IH3 to IH1 (16) and cause inhibition, rather than stimulation, of ATPase activity.…”

mentioning

confidence: 99%

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Locking Intracellular Helices 2 and 3 Together Inactivates Human P-glycoprotein

Loo

Clarke

2014

Journal of Biological Chemistry

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Background: P-glycoprotein is an ATP-dependent drug pump. Results: Mutations or cross-linking of intracellular loops (ICL) 2 and 3 inhibit folding and/or activity. Conclusion: Hydrophobic residues in ICL2 and ICL3 and the second nucleotide-binding domain form a hydrophobic transmission network for folding and activity. Significance: We identify a dual-purpose transmission interface required for folding and activity.

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mentioning

confidence: 64%

“…5A). These results show that maturation of P-gp was more sensitive to changes to Tyr 1087 compared with Phe 1086 because the F1086L mutation did not inhibit maturation (16).…”

Section: Mutating Aromatic Residues Trpmentioning

confidence: 80%

Section: Mutations To Hydrophobic Residues In Ih3 and Flankingmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Locking Intracellular Helices 2 and 3 Together Inactivates Human P-glycoprotein

Loo

Clarke

2014

Journal of Biological Chemistry

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Lemon‐Derived Extracellular Vesicles Nanodrugs Enable to Efficiently Overcome Cancer Multidrug Resistance by Endocytosis‐Triggered Energy Dissipation and Energy Production Reduction

Xiao

Zhao

et al. 2022

Advanced Science

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Multidrug resistance remains a great challenge for cancer chemotherapy. Herein, a biomimetic drug delivery system based on lemon-derived extracellular vesicles (EVs) nanodrugs (marked with heparin-cRGD-EVs-doxorubicin (HRED)) is demonstrated, achieving highly efficient overcoming cancer multidrug resistance. The HRED is fabricated by modifying functional heparin-cRGD (HR) onto the surface of EVs and then by loading with doxorubicin (DOX). The obtained HRED enable to effectively enter DOX-resistant cancer cells by caveolin-mediated endocytosis (main), macropinocytosis (secondary), and clathrin-mediated endocytosis (last), exhibiting excellent cellular uptake capacity. The diversified endocytosis capacity of HRED can efficiently dissipate intracellular energy and meanwhile trigger downstream production reduction of adenosine triphosphate (ATP), leading to a significant reduction of drug efflux. Consequently, they show excellent anti-proliferation capacities to DOX-resistant ovarian cancer, ensuring the efficiently overcoming ovarian cancer multidrug resistance in vivo. The authors believe this strategy provides a new strategy by endocytosis triggered-energy dissipation and ATP production reduction to design drug delivery system for overcoming cancer multidrug resistance.

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Folding correction of ABC‐transporter ABCB1 by pharmacological chaperones: a mechanistic concept

Spork

Sohail

Schmid

et al. 2017

Pharmacology Res & Perspec

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Point mutations of ATP‐binding cassette (ABC) proteins are a common cause of human diseases. Available crystal structures indicate a similarity in the architecture of several members of this protein family. Their molecular architecture makes these proteins vulnerable to mutation, when critical structural elements are affected. The latter preferentially involve the two transmembrane domain (TMD)/nucleotide‐binding domain (NBD) interfaces (transmission interfaces), formation of which requires engagement of coupling helices of intracellular loops with NBDs. Both, formation of the active sites and engagement of the coupling helices, are contingent on correct positioning of ICLs 2 and 4 and thus an important prerequisite for proper folding. Here, we show that active site compounds are capable of rescuing P‐glycoprotein (P‐gp) mutants ∆Y490 and ∆Y1133 in a concentration‐dependent manner. These trafficking deficient mutations are located at the transmission interface in pseudosymmetric position to each other. In addition, the ability of propafenone analogs to correct folding correlates with their ability to inhibit transport of model substrates. This finding indicates that folding correction and transport inhibition by propafenone analogs are brought about by binding to the active sites. Furthermore, this study demonstrates an asymmetry in folding correction with cis‐flupentixol, which reflects the asymmetric binding properties of this modulator to P‐gp. Our results suggest a mechanistic model for corrector action in a model ABC transporter based on insights into the molecular architecture of these transporters.

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Human P-glycoprotein Contains a Greasy Ball-and-Socket Joint at the Second Transmission Interface

Cited by 41 publications

References 41 publications

Locking Intracellular Helices 2 and 3 Together Inactivates Human P-glycoprotein

Locking Intracellular Helices 2 and 3 Together Inactivates Human P-glycoprotein

Lemon‐Derived Extracellular Vesicles Nanodrugs Enable to Efficiently Overcome Cancer Multidrug Resistance by Endocytosis‐Triggered Energy Dissipation and Energy Production Reduction

Folding correction of ABC‐transporter ABCB1 by pharmacological chaperones: a mechanistic concept

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