Crystal structure of the human sterol transporter ABCG5/ABCG8

Lee, Jyh-Yeuan; Kinch, Lisa N.; Borek, Dominika M.; Wang, Jin; Wang, Junmei; Urbatsch, Ina L.; Xie, Xiao-Song; Grishin, Nikolai V.; Cohen, Jonathan C.; Otwinowski, Zbyszek; Hobbs, Helen H.; Rosenbaum, Daniel M.

doi:10.1038/nature17666

Title: Crystal structure of the human sterol transporter ABCG5/ABCG8

Journal Article · Wed May 04 00:00:00 EDT 2016 · Nature (London)

DOI:https://doi.org/10.1038/nature17666· OSTI ID:1255303

Lee, Jyh-Yeuan ^[1]; Kinch, Lisa N. ^[1]; Borek, Dominika M. ^[1]; Wang, Jin ^[1]; Wang, Junmei ^[1]; Urbatsch, Ina L. ^[2]; Xie, Xiao-Song ^[1]; Grishin, Nikolai V. ^[1]; Cohen, Jonathan C. ^[1]; Otwinowski, Zbyszek ^[1]; Hobbs, Helen H. ^[1]; Rosenbaum, Daniel M. ^[1]

Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
Texas Tech Univ. Health Sciences Center, Lubbock, TX (United States)

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. 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 Å 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. Here, 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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; American Heart Association South Central Affiliate; American Heart Association Texas Affiliate; Welch Foundation; Packard Foundation; Howard Hughes Medical Inst.; National Inst. of Health

Grant/Contract Number:: AC02-06CH11357; 0825285F; 0463130Y; I-1770; HL72304; P01-HL20948; GM094575; GM053163; GM117080; GM113050

OSTI ID:: 1255303

Journal Information:: Nature (London), Vol. 533, Issue 7604; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 199 works

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All about CDR transporters: Past, present, and future Prasad, Rajendra; Balzi, Elisabetta; Banerjee, Atanu Yeast, Vol. 36, Issue 4 https://doi.org/10.1002/yea.3356	journal	October 2018
Mechanics and pharmacology of substrate selection and transport by eukaryotic ABC exporters Srikant, Sriram; Gaudet, Rachelle Nature Structural & Molecular Biology, Vol. 26, Issue 9 https://doi.org/10.1038/s41594-019-0280-4	journal	August 2019
On the use of Pichia pastoris for isotopic labeling of human GPCRs for NMR studies Clark, Lindsay; Dikiy, Igor; Rosenbaum, Daniel M. Journal of Biomolecular NMR, Vol. 71, Issue 4 https://doi.org/10.1007/s10858-018-0204-3	journal	August 2018
ABCG5 and ABCG8: more than a defense against xenosterols Patel, Shailendra B.; Graf, Gregory A.; Temel, Ryan E. Journal of Lipid Research, Vol. 59, Issue 7 https://doi.org/10.1194/jlr.r084244	journal	May 2018
Structure of the human multidrug transporter ABCG2 Taylor, Nicholas M. I.; Manolaridis, Ioannis; Jackson, Scott M. Nature, Vol. 546, Issue 7659 https://doi.org/10.1038/nature22345	journal	May 2017
Expression of multidrug transporter P‐glycoprotein in Pichia pastoris affects the host's methanol metabolism Liu, Wan‐cang; Zhou, Fei; Xia, Di Microbial Biotechnology, Vol. 12, Issue 6 https://doi.org/10.1111/1751-7915.13420	journal	May 2019
PBDE-47 and PBDE mixture (DE-71) toxicities and liver transcriptomic changes at PND 22 after in utero/postnatal exposure in the rat Dunnick, J. K.; Shockley, K. R.; Pandiri, A. R. Archives of Toxicology, Vol. 92, Issue 11 https://doi.org/10.1007/s00204-018-2292-y	journal	September 2018
Application of High-Throughput Sequencing in the Diagnosis of Inherited Thrombocytopenia Wang, Qi; Cao, Lijuan; Sheng, Guangying Clinical and Applied Thrombosis/Hemostasis, Vol. 24, Issue 9_suppl https://doi.org/10.1177/1076029618790696	journal	July 2018
Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis El Kasmi, Karim C.; Vue, Padade M.; Anderson, Aimee L. Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-03764-1	journal	April 2018
Architecture of a channel-forming O-antigen polysaccharide ABC transporter Bi, Yunchen; Mann, Evan; Whitfield, Chris Nature, Vol. 553, Issue 7688 https://doi.org/10.1038/nature25190	journal	January 2018
Antibiotic Resistance Mediated by the MacB ABC Transporter Family: A Structural and Functional Perspective. Greene, Nicholas; Kaplan, Elise; Crow, Allister Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.26693	text	January 2018
Structural Biology and Structure–Function Relationships of Membrane Proteins Moraes, Isabel; Quigley, Andrew Biology, Vol. 10, Issue 3 https://doi.org/10.3390/biology10030245	journal	March 2021
Structural basis of small-molecule inhibition of human multidrug transporter ABCG2 Jackson, Scott M.; Manolaridis, Ioannis; Kowal, Julia ETH Zurich https://doi.org/10.3929/ethz-b-000256191	text	January 2018
Quantitative comparison of ABC membrane protein type I exporter structures in a standardized way Csizmadia, Georgina; Farkas, Bianka; Spagina, Zoltán Computational and Structural Biotechnology Journal, Vol. 16 https://doi.org/10.1016/j.csbj.2018.10.008	journal	January 2018
Structure of the MacAB–TolC ABC-type tripartite multidrug efflux pump Fitzpatrick, Anthony W. P.; Llabrés, Salomé; Neuberger, Arthur Nature Microbiology, Vol. 2, Issue 7 https://doi.org/10.1038/nmicrobiol.2017.70	journal	May 2017
3D structure of the transporter ABCG2—What's new? Eckenstaler, Robert; Benndorf, Ralf A. British Journal of Pharmacology, Vol. 177, Issue 7 https://doi.org/10.1111/bph.14991	journal	February 2020
Jump into a New Fold—A Homology Based Model for the ABCG2/BCRP Multidrug Transporter László, Laura; Sarkadi, Balázs; Hegedűs, Tamás PLOS ONE, Vol. 11, Issue 10 https://doi.org/10.1371/journal.pone.0164426	journal	October 2016
X-ray diffraction reveals the intrinsic difference in the physical properties of membrane and soluble proteins. Robert, Xavier; Kassis-Sahyoun, Josiane; Ceres, Nicoletta Springer Science and Business Media LLC https://doi.org/10.17863/cam.22258	journalarticle	January 2017
Relationship between conformation shift and disease related variation sites in ATP-binding cassette transporter proteins Sakamoto, Mika; Suzuki, Hirofumi; Yura, Kei Biophysics and Physicobiology, Vol. 16, Issue 0 https://doi.org/10.2142/biophysico.16.0_68	journal	January 2019
ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches Cleophas, Maartje; Joosten, Leo; Stamp, Lisa Pharmacogenomics and Personalized Medicine, Vol. Volume 10 https://doi.org/10.2147/pgpm.s105854	journal	April 2017
Disruption of the Unique ABCG-Family NBD:NBD Interface Impacts Both Drug Transport and ATP Hydrolysis Kapoor, Parth; Briggs, Deborah A.; Cox, Megan H. International Journal of Molecular Sciences, Vol. 21, Issue 3 https://doi.org/10.3390/ijms21030759	journal	January 2020

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