NDLI: Repacking of the transmembrane domains of P-glycoprotein during the transport ATPase cycle

Content Provider	PubMed Central
Author	Rosenberg, Mark F. Velarde, Giles Ford, Robert C. Martin, Catherine Berridge, Georgina Kerr, Ian D. Callaghan, Richard Schmidlin, Andreas Wooding, Carol Linton, Kenneth J. Higgins, Christopher F.
Copyright Year	2001
Abstract	P-glycoprotein (P-gp) is an ABC (ATP-binding cassette) transporter, which hydrolyses ATP and extrudes cytotoxic drugs from mammalian cells. P-gp consists of two transmembrane domains (TMDs) that span the membrane multiple times, and two cytoplasmic nucleotide-binding domains (NBDs). We have determined projection structures of P-gp trapped at different steps of the transport cycle and correlated these structures with function. In the absence of nucleotide, an ∼10 Å resolution structure was determined by electron cryo-microscopy of two-dimensional crystals. The TMDs form a chamber within the membrane that appears to be open to the extracellular milieu, and may also be accessible from the lipid phase at the interfaces between the two TMDs. Nucleotide binding causes a repacking of the TMDs and reduction in drug binding affinity. Thus, ATP binding, not hydrolysis, drives the major conformational change associated with solute translocation. A third distinct conformation of the protein was observed in the post-hydrolytic transition state prior to release of ADP/Pi. Biochemical data suggest that these rearrangements may involve rotation of transmembrane α-helices. A mechanism for transport is suggested.
Related Links	http://dx.doi.org/10.1093/emboj/20.20.5615
Ending Page	5625
Page Count	11
Starting Page	5615
File Format	PDF
ISSN	14602075
e-ISSN	14602075
Journal	The EMBO Journal
Issue Number	20
Volume Number	20
Language	English
Publisher	Oxford University Press
Publisher Date	2001-10-15
Access Restriction	Open
Rights Holder	Oxford University Press
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Immunology and Microbiology(all) Neuroscience(all) Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Microbiology Medicine Molecular Biology

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