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Reversing the direction of drug transport mediated by the human multidrug transporter P-glycoprotein.
Sajid, Andaleeb; Lusvarghi, Sabrina; Murakami, Megumi; Chufan, Eduardo E; Abel, Biebele; Gottesman, Michael M; Durell, Stewart R; Ambudkar, Suresh V.
Afiliação
  • Sajid A; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
  • Lusvarghi S; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
  • Murakami M; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
  • Chufan EE; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
  • Abel B; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
  • Gottesman MM; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
  • Durell SR; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
  • Ambudkar SV; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892 ambudkar@mail.nih.gov.
Proc Natl Acad Sci U S A ; 117(47): 29609-29617, 2020 11 24.
Article em En | MEDLINE | ID: mdl-33168729
ABSTRACT
P-glycoprotein (P-gp), also known as ABCB1, is a cell membrane transporter that mediates the efflux of chemically dissimilar amphipathic drugs and confers resistance to chemotherapy in most cancers. Homologous transmembrane helices (TMHs) 6 and 12 of human P-gp connect the transmembrane domains with its nucleotide-binding domains, and several residues in these TMHs contribute to the drug-binding pocket. To investigate the role of these helices in the transport function of P-gp, we substituted a group of 14 conserved residues (seven in both TMHs 6 and 12) with alanine and generated a mutant termed 14A. Although the 14A mutant lost the ability to pump most of the substrates tested out of cancer cells, surprisingly, it acquired a new function. It was able to import four substrates, including rhodamine 123 (Rh123) and the taxol derivative flutax-1. Similar to the efflux function of wild-type P-gp, we found that uptake by the 14A mutant is ATP hydrolysis-, substrate concentration-, and time-dependent. Consistent with the uptake function, the mutant P-gp also hypersensitizes HeLa cells to Rh123 by 2- to 2.5-fold. Further mutagenesis identified residues from both TMHs 6 and 12 that synergistically form a switch in the central region of the two helices that governs whether a given substrate is pumped out of or into the cell. Transforming P-gp or an ABC drug exporter from an efflux transporter into a drug uptake pump would constitute a paradigm shift in efforts to overcome cancer drug resistance.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transporte Biológico / Preparações Farmacêuticas / Membro 1 da Subfamília B de Cassetes de Ligação de ATP / Resistência a Múltiplos Medicamentos Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transporte Biológico / Preparações Farmacêuticas / Membro 1 da Subfamília B de Cassetes de Ligação de ATP / Resistência a Múltiplos Medicamentos Idioma: En Ano de publicação: 2020 Tipo de documento: Article