How does P-glycoprotein recognize its substrates?

Ueda, Kazumitsu; Taguchi, Yoshitomo; Miyamoto, Masaki

doi:10.1006/scbi.1997.0066

Cited by 107 publications

(80 citation statements)

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“…Their ability to be recognized by Pgp therefore may be a function of relative hydrophobicity, rather than the structural requirements outlined above (Ueda et al, 1997). The ability of these steroids to modulate Pgp also appears to follow the same pattern observed for substrate recognition.…”

Section: Whereas Both Therapeutic Classes Inhibit Rh123 Efflux With Imentioning

confidence: 86%

Modulation of P-glycoprotein activity in Calu-3 cells using steroids and β-ligands

Hamilton

Yazdanian

Audus

2001

International Journal of Pharmaceutics

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Section: Whereas Both Therapeutic Classes Inhibit Rh123 Efflux With Imentioning

confidence: 86%

Modulation of P-glycoprotein activity in Calu-3 cells using steroids and β-ligands

Hamilton

Yazdanian

Audus

2001

International Journal of Pharmaceutics

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“…Its expression in cancer cells confers a drug resistant phenotype [2,3] by preventing the accumulation of chemotherapy agents to cytotoxic levels. P-gp is capable of binding and/or transporting an astonishing number of chemically distinct compounds, whose only similarities include hydrophobicity, a planar ring system and often, the presence of a cationic nitrogen moiety [4][5][6]. This poly-specificity exhibited by P-gp remains an enigmatic feature that has eluded a molecular description to date.…”

Section: Introductionmentioning

confidence: 99%

Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein

Mittra

Pavy

Subramanian

et al. 2017

Biochemical Pharmacology

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The multidrug resistance P-glycoprotein (P-gp) is characterised by the ability to bind and/or transport an astonishing array of drugs. This poly-specificity is imparted by at least four pharmacologically distinct binding sites within the transmembrane domain. Whether or not these sites are spatially distinct has remained unclear. Biochemical and structural investigations have implicated a central cavity as the likely location for the binding sites. In the present investigation, a number of contact residues that are involved in drug binding were identified through biochemical assays using purified, reconstituted P-gp. Drugs were selected to represent each of the four pharmacologically distinct sites. Contact residues important in rhodamine123 binding were identified in the central cavity of P-gp. However, contact residues for the binding of vinblastine, paclitaxel and nicardipine were located at the lipid-protein interface rather than the central cavity. A key residue (F978) within the central cavity is believed to be involved in coupling drug binding to nucleotide hydrolysis. Data observed in this investigation suggest the presence of spatially distinct drug binding sites connecting through to a single translocation pore in the central cavity.

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“…(7,8,11). Interestingly, a similar range of drugs and modulators was also found to interact with human P-glycoprotein (12).…”

Section: Substrate Specificitymentioning

confidence: 88%

Bacterial Multidrug Resistance Mediated by a Homologue of the Human Multidrug Transporter P‐glycoprotein

Konings

Poelarends

2002

IUBMB Life

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SummaryMost ATP-binding cassette (ABC) multidrug transporters known to date are of eukaryotic origin, such as the P-glycoproteins (Pgps) and multidrug resistance-associated proteins (MRPs). Only one well-characterized ABC multidrug transporter, LmrA, is of bacterial origin. On the basis of its structural and functional characteristics, this bacterial protein is classified as a member of the P-glycoprotein cluster of the ABC transporter superfamily. LmrA can even substitute for P-glycoprotein in human lung fibroblast cells, suggesting that this type of transporter is conserved from bacteria to man. The functional similarity between bacterial LmrA and human P-glycoprotein is further exemplified by their currently known spectrum of substrates, consisting mainly of hydrophobic cationic compounds. In addition, LmrA was found to confer resistance to eight classes of broad-spectrum antibiotics, and homologs of LmrA have been found in pathogenic bacteria, supporting the clinical and academic value of studying this bacterial protein. Current studies are focused on unraveling the mechanism by which ABC multidrug transporters, such as LmrA, couple the hydrolysis of ATP to the translocation of drugs across the membrane. Recent evidence indicates that LmrA mediates drug transport by an alternating two-site transport mechanism. IUBMB Life, 53: 213-218, 2002

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How does P-glycoprotein recognize its substrates?

Cited by 107 publications

References 0 publications

Modulation of P-glycoprotein activity in Calu-3 cells using steroids and β-ligands

Modulation of P-glycoprotein activity in Calu-3 cells using steroids and β-ligands

Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein

Bacterial Multidrug Resistance Mediated by a Homologue of the Human Multidrug Transporter P‐glycoprotein

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