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PDBsum entry 4f4c
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Hydrolase,protein transport
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PDB id
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4f4c
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the multidrug transporter p-Glycoprotein from caenorhabditis elegans.
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Authors
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M.S.Jin,
M.L.Oldham,
Q.Zhang,
J.Chen.
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Ref.
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Nature, 2012,
490,
566-569.
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PubMed id
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Abstract
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P-glycoprotein (P-gp) is an ATP-binding cassette transporter that confers
multidrug resistance in cancer cells. It also affects the absorption,
distribution and clearance of cancer-unrelated drugs and xenobiotics. For these
reasons, the structure and function of P-gp have been studied extensively for
decades. Here we present biochemical characterization of P-gp from
Caenorhabditis elegans and its crystal structure at a resolution of
3.4 ångströms. We find that the apparent affinities of P-gp for anticancer
drugs actinomycin D and paclitaxel are approximately 4,000 and 100 times
higher, respectively, in the membrane bilayer than in detergent. This affinity
enhancement highlights the importance of membrane partitioning when a drug
accesses the transporter in the membrane. Furthermore, the transporter in the
crystal structure opens its drug pathway at the level of the membrane's inner
leaflet. In the helices flanking the opening to the membrane, we observe
extended loops that may mediate drug binding, function as hinges to gate the
pathway or both. We also find that the interface between the transmembrane and
nucleotide-binding domains, which couples ATP hydrolysis to transport, contains
a ball-and-socket joint and salt bridges similar to the ATP-binding cassette
importers, suggesting that ATP-binding cassette exporters and importers may use
similar mechanisms to achieve alternating access for transport. Finally, a model
of human P-gp derived from the structure of C. elegans P-gp not only is
compatible with decades of biochemical analysis, but also helps to explain
perplexing functional data regarding the Phe335Ala mutant. These results
increase our understanding of the structure and function of this important
molecule.
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