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Structural basis for gating mechanisms of a eukaryotic P-glycoprotein homolog.


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.

SUBMITTER: Kodan A 

PROVIDER: S-EPMC3964115 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Structural basis for gating mechanisms of a eukaryotic P-glycoprotein homolog.

Kodan Atsushi A   Yamaguchi Tomohiro T   Nakatsu Toru T   Sakiyama Keita K   Hipolito Christopher J CJ   Fujioka Akane A   Hirokane Ryo R   Ikeguchi Keiji K   Watanabe Bunta B   Hiratake Jun J   Kimura Yasuhisa Y   Suga Hiroaki H   Ueda Kazumitsu K   Kato Hiroaki H  

Proceedings of the National Academy of Sciences of the United States of America 20140303 11


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 o  ...[more]

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