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Evidence for a Sav1866‐like architecture for the human multidrug transporter P‐glycoprotein
Author(s) -
Zolnerciks Joseph K.,
Wooding Carol,
Linton Kenneth J.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-8610com
Subject(s) - atp binding cassette transporter , cyclic nucleotide binding domain , transporter , transmembrane domain , multiple drug resistance , multidrug resistance associated proteins , transmembrane protein , computational biology , biology , mutagenesis , p glycoprotein , glycoprotein , domain (mathematical analysis) , plasma protein binding , microbiology and biotechnology , biochemistry , nucleotide , gene , mutation , receptor , mathematical analysis , mathematics , antibiotics
The recently reported structures of the bacterial multidrug exporter Sav1866 suggest a domain architecture in which both nucleotide‐binding domains (NBDs) of this ATP binding cassette (ABC) transporter contact both transmembrane domains (TMDs). Such a domain arrangement is particularly unexpected because it is not found in the structures of three solute importers BtuCD, HI1470/1, and ModBC from the same protein family. There is also no precedent for such an arrangement from biochemical studies with any ABC transporter. Sav1866 is homologous with the clinically relevant human P‐glycoprotein (ABCB1). If the structure proposed for Sav1866 is physiologically relevant, the long intracellular loops of P‐glycoprotein TMD2 should contact NBD1. We have tested this by using cysteine mutagenesis and chemical cross‐linking to verify proximal relationships of the introduced sulfhydryls across the proposed interdomain interface. We report the first biochemical evidence in support of the domain arrangement proposed for the multidrug resistance class of ABC transporters. With a domain arrangement distinctly different from the three solute importers it seems likely that the TMDs of ABC importers and exporters have evolved different mechanisms to couple to common conformational changes at conserved NBDs.— Zolnerciks, J. K., Wooding, C., Linton, K. J. Evidence for a Sav1866‐like architecture for the human multidrug transporter P‐glycoprotein. FASEB J . 21, 3937–3948 (2007)