The P-glycoprotein multidrug transporter: interactions with membrane lipids, and their modulation of activity

1997 ◽  
Vol 25 (3) ◽  
pp. 1088-1096 ◽  
Author(s):  
F. J. Sharom
Keyword(s):  
Membrane Lipids ◽  
Multidrug Transporter ◽  
P Glycoprotein

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

2021 ◽  
Author(s):  
Karan Kapoor ◽  
Shashank Pant ◽  
Emad Tajkhorshid
Keyword(s):  
Membrane Lipids ◽  
Active Participation ◽  
Multidrug Transporter ◽  
Glycoprotein P ◽  
P Glycoprotein

Lipid invasion of P-glycoprotein, enhanced by binding of an inhibitor.

scholarly journals Mouse-Human Chimeric Antibody MH171 against the Multidrug Transporter P-Glycoprotein

1992 ◽  
Vol 83 (5) ◽  
pp. 515-521 ◽  
Author(s):  
Keiko Ariyoshi ◽  
Hirofumi Hamada ◽  
Mikihiko Naito ◽  
Yuji Heike ◽  
Hiroyuki Seimiya ◽  
...  
Keyword(s):  
Chimeric Antibody ◽  
Multidrug Transporter ◽  
P Glycoprotein

Kinetics of the multidrug transporter (P-glycoprotein) and its reversal

1997 ◽  
Vol 77 (2) ◽  
pp. 545-590 ◽  
Author(s):  
W. D. Stein
Keyword(s):  
Final Section ◽  
Transport Kinetics ◽  
Multidrug Transporter ◽  
Chemotherapeutic Drugs ◽  
Multidrug Resistance Proteins ◽  
Binding Properties ◽  
Membrane Pump ◽  
Resistance Proteins ◽  
P Glycoprotein ◽  
Kinetics Of

Most cancer deaths result from the cancer's either being intrinsically resistant to chemotherapeutic drugs or becoming resistant after being initially sensitive. Often, in cells grown in cell culture, drug resistance correlates with the presence of one or more of the so-called P-glycoproteins or multidrug resistance proteins, products of the mdr family of genes. This review is largely concerned with the transport kinetics of the P-glycoproteins. We first present a brief overview of the P-glycoproteins, their properties, and their clinical significance. Later sections of the review expand on this material with special emphasis on the substrates of P-glycoprotein and how they cross the cell membrane, on the transport kinetics of the P-glycoprotein, on reversers of its action, and on its activity as an ATPase. In a final section, we consider the mechanism of action of P-glycoprotein as an actively transporting membrane pump. The characteristic of P-glycoprotein considered the most difficult to explain is its very broad specificity (or lack of specificity), but there are precedents for this property in well-known proteins such as serum albumin, which binds a range of molecular types, including substrates and reversers of P-glycoprotein, seemingly as broad as does P-glycoprotein. Pointing out this analogy does not provide a molecular explanation for the substrate-binding properties of P-glycoprotein but does make those properties more assimilable.

scholarly journals Characterization and tissue localization of zebrafish homologs of the human ABCB1 multidrug transporter

2021 ◽  
Author(s):  
Robert W. Robey ◽  
Andrea N. Robinson ◽  
Fatima Ali-Rahmani ◽  
Lyn M. Huff ◽  
Sabrina Lusvarghi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Multidrug Transporter ◽  
Glycoprotein P ◽  
Tissue Localization ◽  
Brain Vasculature ◽  
P Glycoprotein ◽  
Capillary Endothelial Cells ◽  
The Brain ◽  
Viable Model

ABSTRACTGiven its similarities with mammalian systems, the zebrafish has emerged as a potential model to study the blood-brain barrier (BBB). Capillary endothelial cells at the human BBB express high levels of P-glycoprotein (P-gp, encoded by the ABCB1 gene) and ABCG2 (encoded by the ABCG2 gene). However, little information has been available about ATP-binding cassette transporters expressed at the zebrafish BBB. In this study, we focus on the characterization and tissue localization of two genes that are similar to human ABCB1, zebrafish abcb4 and abcb5. Cytotoxicity assays with stably-transfected cell lines revealed that zebrafish Abcb5 cannot efficiently transport the substrates doxorubicin and mitoxantrone compared to human P-gp and zebrafish Abcb4. Additionally, zebrafish Abcb5 did not transport the fluorescent probes BODIPY-ethylenediamine or LDS 751, while they were readily transported by Abcb4 and P-gp. A high-throughput screen conducted with 90 human P-gp substrates confirmed that zebrafish Abcb4 has overlapping substrate specificity with P-gp. Basal ATPase activity of zebrafish Abcb4 and Abcb5 was comparable to that of human P-gp. In the brain vasculature, RNAscope probes to detect abcb4 colocalized with staining by the P-gp antibody C219, while abcb5 was not detected. Zebrafish abcb4 also colocalized with claudin-5 expression in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, consistent with different functions. The data suggest that zebrafish Abcb4 most closely phenocopies P-gp and that the zebrafish may be a viable model to study the role of the multidrug transporter P-gp at the BBB.

scholarly journals Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1

2018 ◽  
Vol 115 (9) ◽  
pp. E1973-E1982 ◽  
Author(s):  
Amer Alam ◽  
Raphael Küng ◽  
Julia Kowal ◽  
Robert A. McLeod ◽  
Nina Tremp ◽  
...  
Keyword(s):  
Lipid Membrane ◽  
Binding Pocket ◽  
Conformational Epitope ◽  
Multidrug Transporter ◽  
Inhibitory Antibody ◽  
Binding Domains ◽  
Atp Binding Cassette Transporter ◽  
P Glycoprotein ◽  
Inhibitory Agents ◽  
Human Specific

The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes.

Phospholipid Flippase Activity of the Reconstituted P-Glycoprotein Multidrug Transporter†

Biochemistry ◽  
2001 ◽  
Vol 40 (23) ◽  
pp. 6937-6947 ◽  
Author(s):  
Yolanda Romsicki ◽  
Frances J. Sharom
Keyword(s):  
Multidrug Transporter ◽  
P Glycoprotein ◽  
Phospholipid Flippase
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