Science (American Association for the Advancement of Science), 2019-02, Vol.363 (6428), p.753-756
2019
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- Autor(en) / Beteiligte
- Titel
- Structural insight into substrate and inhibitor discrimination by human P-glycoprotein
- Ist Teil von
- Science (American Association for the Advancement of Science), 2019-02, Vol.363 (6428), p.753-756
- Ort / Verlag
- United States: The American Association for the Advancement of Science
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic drug delivery. We determined the 3.5-angstrom cryo-electron microscopy structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the adenosine triphosphate-hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0036-8075eISSN: 1095-9203DOI: 10.1126/science.aav7102Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6800160
- Format
- –
- Schlagworte
- Adenosine triphosphate, Adenosine Triphosphate - chemistry, Animals, Antineoplastic Agents, Phytogenic - chemistry, Antineoplastic Agents, Phytogenic - pharmacology, ATP, ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily B - chemistry, Binding Sites, Cancer, Cholesterol, Cholesterol - chemistry, Cryoelectron Microscopy, Dibenzocycloheptenes - chemistry, Dibenzocycloheptenes - pharmacology, Domains, Drug delivery, Drug delivery systems, Drug Design, Drug resistance, Electron microscopy, Glycoproteins, Humans, Hydrolysis, Inhibitors, Membrane proteins, Mice, Microscopy, Mutant Chimeric Proteins - antagonists & inhibitors, P-Glycoprotein, Paclitaxel, Paclitaxel - chemistry, Paclitaxel - pharmacology, Phospholipids, Phospholipids - chemistry, Protein Binding, Protein Domains - drug effects, Proteins, Quinolines - chemistry, Quinolines - pharmacology, Substrate inhibition, Substrate Specificity, Substrates, Taxol, Transport