期刊
NATURE
卷 533, 期 7604, 页码 561-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature17666
关键词
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资金
- American Heart Association South Central Affiliate- [0825285F]
- American Heart Association Texas Affiliate [0463130Y]
- Welch Foundation [I-1770]
- Packard Foundation
- Howard Hughes Medical Institute
- National Institutes of Health [HL72304, P01-HL20948, GM094575, GM053163, GM117080, GM113050]
ATP binding cassette (ABC) transporters play critical roles in maintaining sterol balance in higher eukaryotes. The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols in liver and intestines(1-5). Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Here we use crystallization in lipid bilayers to determine the X-ray structure of human G5G8 in a nucleotide-free state at 3.9 angstrom resolution, generating the first atomic model of an ABC sterol transporter. The structure reveals a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter. The G5G8 structure provides a mechanistic framework for understanding sterol transport and the disruptive effects of mutations causing sitosterolaemia.
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