Abstract:
:P-glycoprotein is an ATP-binding cassette multidrug transporter that actively transports chemically diverse substrates across the lipid bilayer. The precise molecular mechanism underlying transport is not fully understood. Here, we present crystal structures of a eukaryotic P-glycoprotein homolog, CmABCB1 from Cyanidioschyzon merolae, in two forms: unbound at 2.6-Å resolution and bound to a unique allosteric inhibitor at 2.4-Å resolution. The inhibitor clamps the transmembrane helices from the outside, fixing the CmABCB1 structure in an inward-open conformation similar to the unbound structure, confirming that an outward-opening motion is required for ATP hydrolysis cycle. These structures, along with site-directed mutagenesis and transporter activity measurements, reveal the detailed architecture of the transporter, including a gate that opens to extracellular side and two gates that open to intramembranous region and the cytosolic side. We propose that the motion of the nucleotide-binding domain drives those gating apparatuses via two short intracellular helices, IH1 and IH2, and two transmembrane helices, TM2 and TM5.
journal_name
Proc Natl Acad Sci U S Aauthors
Kodan A,Yamaguchi T,Nakatsu T,Sakiyama K,Hipolito CJ,Fujioka A,Hirokane R,Ikeguchi K,Watanabe B,Hiratake J,Kimura Y,Suga H,Ueda K,Kato Hdoi
10.1073/pnas.1321562111subject
Has Abstractpub_date
2014-03-18 00:00:00pages
4049-54issue
11eissn
0027-8424issn
1091-6490pii
1321562111journal_volume
111pub_type
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