Details

Autor(en) / Beteiligte

• Dastvan, Reza
• Mishra, Smriti
• Peskova, Yelena B
• Nakamoto, Robert K
• Mchaourab, Hassane S

Titel

Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors

Ist Teil von

• Science (American Association for the Advancement of Science), 2019-05, Vol.364 (6441), p.689-692

Ort / Verlag

United States: The American Association for the Advancement of Science

Erscheinungsjahr

2019

Link zum Volltext

Quelle

American Association for the Advancement of Science

Beschreibungen/Notizen

• The ATP-binding cassette subfamily B member 1 (ABCB1) multidrug transporter P-glycoprotein plays a central role in clearance of xenobiotics in humans and is implicated in cancer resistance to chemotherapy. We used double electron electron resonance spectroscopy to uncover the basis of stimulation of P-glycoprotein adenosine 5'-triphosphate (ATP) hydrolysis by multiple substrates and illuminate how substrates and inhibitors differentially affect its transport function. Our results reveal that substrate-induced acceleration of ATP hydrolysis correlates with stabilization of a high-energy, post-ATP hydrolysis state characterized by structurally asymmetric nucleotide-binding sites. By contrast, this state is destabilized in the substrate-free cycle and by high-affinity inhibitors in favor of structurally symmetric nucleotide binding sites. Together with previous data, our findings lead to a general model of substrate and inhibitor coupling to P-glycoprotein.