Crystal structure of the human sterol transporter ABCG5/ABCG8

Article

关键词: PROTEIN-SEQUENCE ALIGNMENT;    ABC TRANSPORTER;    DROSOPHILA-MELANOGASTER;    DIFFRACTION INTENSITIES;    DENSITY MODIFICATION;    DIETARY-CHOLESTEROL;    MALTOSE TRANSPORTER;    MEMBRANE-PROTEINS;    BINDING-PROTEIN;    FORCE-FIELD;   

DOI  :  10.1038/nature17666

来源: SCIE

【 摘 要 】

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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