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.

authors

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 H

doi

10.1073/pnas.1321562111

subject

Has Abstract

pub_date

2014-03-18 00:00:00

pages

4049-54

issue

11

eissn

0027-8424

issn

1091-6490

pii

1321562111

journal_volume

111

pub_type

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