Structural insight into substrate and inhibitor discrimination by human P-glycoprotein | Zendy

Amer Alam | Zendy; Julia Kowal | Zendy; Eugenia V. Broude | Zendy; Igor B. Roninson | Zendy; Kaspar P. Locher | Zendy

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Structural insight into substrate and inhibitor discrimination by human P-glycoprotein

Author(s) -

Amer Alam,

Julia Kowal,

Eugenia V. Broude,

Igor B. Roninson,

Kaspar P. Locher

Publication year - 2019

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aav7102

Subject(s) - binding site , plasma protein binding , biophysics , phospholipid , chemistry , atp binding cassette transporter , biochemistry , substrate (aquarium) , cryo electron microscopy , xenobiotic , transporter , membrane , biology , enzyme , ecology , gene

To transport or not to transport Therapeutic drug delivery into cells is complicated by membrane proteins like ABCB1 (also termed P-glycoprotein) that shuttle diverse compounds out of cells. Alamet al. determined high-resolution cryo–electron microscopy structures of ABCB1 bound either to a substrate, the cancer drug Taxol, or to the ABCB1 inhibitor zosuquidar. The conformational changes that facilitate drug transport are caused by hydrolysis of adenosine triphosphate (ATP). The structures show that, although Taxol and zosquidar bind to the same site, subtle structural differences lead to altered conformations of the nucleotide binding domains that are responsible for ATP hydrolysis.Science , this issue p.753

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