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

Authors:
; ; ; ; ; ; ; ; ; ; ;  [1];  [2]
  1. TTU
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHAHAOTHERHHMI
OSTI Identifier:
1255303
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature (London); Journal Volume: 533; Journal Issue: 05, 2016
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

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., and UTSMC). Crystal structure of the human sterol transporter ABCG5/ABCG8. United States: N. p., 2016. Web. doi:10.1038/nature17666.
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., & UTSMC). Crystal structure of the human sterol transporter ABCG5/ABCG8. United States. doi:10.1038/nature17666.
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., and UTSMC). 2016. "Crystal structure of the human sterol transporter ABCG5/ABCG8". United States. doi:10.1038/nature17666.
@article{osti_1255303,
title = {Crystal structure of the human sterol transporter ABCG5/ABCG8},
author = {Lee, Jyh-Yeuan and Kinch, Lisa N. and Borek, Dominika M. and Wang, Jin and Wang, Junmei and Urbatsch, Ina L. and Xie, Xiao-Song and Grishin, Nikolai V. and Cohen, Jonathan C. and Otwinowski, Zbyszek and Hobbs, Helen H. and Rosenbaum, Daniel M. and UTSMC)},
abstractNote = {},
doi = {10.1038/nature17666},
journal = {Nature (London)},
number = 05, 2016,
volume = 533,
place = {United States},
year = 2016,
month = 7
}
  • Sterol carrier protein X (SCPx) is a 58-kDa protein that is localized to peroxisomes. The amino acid sequence of the protein suggests that SCPx may function as a thiolase. The gene encoding SCPx also codes for a 15.3-kDa protein called sterol carrier protein 2 (SCP{sub 2}). Here the authors report the structure of this gene (SCP2), which spans approximately 80 kb and consists of 16 exons and 15 introns. Multiple transcription start sites were identified. The 5{prime} flanking region has characteristics of other peroxisomal protein promoters, which include the absence of a TATA box and G+C-enriched region containing several reversemore » GC boxes. 24 refs., 3 figs., 1 tab.« less
  • P-glycoprotein (P-gp) is a polyspecific ATP-dependent transporter linked to multidrug resistance in cancers that plays important roles in the pharmacokinetics of a large number of drugs. The drug-resistance phenotype of P-gp can be modulated by the monoclonal antibody UIC2, which specifically recognizes human P-gp in a conformation-dependent manner. Here, the purification, sequence determination and high-resolution structure of the Fab fragment of UIC2 (UIC2/Fab) are reported. Purified UIC2/Fab binds human P-gp with a 1:1 stoichiometry. Crystals of UIC2/Fab are triclinic (space groupP1), with unit-cell parametersa= 40.67,b= 44.91,c= 58.09 Å, α = 97.62, β = 99.10, γ = 94.09°, and diffracted X-rays tomore » 1.6 Å resolution. The structure was determined by molecular replacement and refined to 1.65 Å resolution. The asymmetric unit contains one molecule of UIC2/Fab, which exhibits a positively charged antigen-binding surface, suggesting that it might recognize an oppositely charged extracellular epitope of P-gp.« less
  • Sterol 14{alpha}-demethylase (14DM, the CYP51 family of cytochrome P450) is an essential enzyme in sterol biosynthesis in eukaryotes. It serves as a major drug target for fungal diseases and can potentially become a target for treatment of human infections with protozoa. Here we present 1.9 {angstrom} resolution crystal structures of 14DM from the protozoan pathogen Trypanosoma brucei, ligand-free and complexed with a strong chemically selected inhibitor N-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(5-phenyl-1,3,4-oxadi-azol-2-yl)benzamide that we previously found to produce potent antiparasitic effects in Trypanosomatidae. This is the first structure of a eukaryotic microsomal 14DM that acts on sterol biosynthesis, and it differs profoundly from that ofmore » the water-soluble CYP51 family member from Mycobacterium tuberculosis, both in organization of the active site cavity and in the substrate access channel location. Inhibitor binding does not cause large scale conformational rearrangements, yet induces unanticipated local alterations in the active site, including formation of a hydrogen bond network that connects, via the inhibitor amide group fragment, two remote functionally essential protein segments and alters the heme environment. The inhibitor binding mode provides a possible explanation for both its functionally irreversible effect on the enzyme activity and its selectivity toward the 14DM from human pathogens versus the human 14DM ortholog. The structures shed new light on 14DM functional conservation and open an excellent opportunity for directed design of novel antiparasitic drugs.« less
  • Sterol regulatory element binding protein-1 (SREBP1) and SREBP2 are structurally related proteins that control cholesterol homeostasis by stimulating transcription of sterol-regulated genes, including those encoding the low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl CoA synthase. SREBP1 and SREBP2 are 47% identical, and they share a novel structure comprising a transcriptionally active NH{sub 2}-terminal basic helix-loop-helix-leucine zipper (bHLH-Zip) domain followed by a membrane attachment domain. Cleavage by a sterol-regulated protease frees the bHLH-Zip domain from the membrane and allows it to enter the nucleus. SREBP1 exists in several forms, possibly as a result of alternative splicing at both the 5{prime} and themore » 3{prime} ends of the mRNA. The genes for SREBP1 (SREBF1) and SREBP2 (SREBF2) have not been studied. In this paper we describe the cloning and characterization of the human SREBF1 gene. The gene is 26 kb in length and has 22 exons and 20 introns. The 5{prime} and 3{prime} sequences that differ between the two SREBP1 cDNAs are encoded by discrete exons, conforming the hypothesis that they result from alternative splicing. The chromosomal locations of human SREBF1 and SREBF2 were determined by analysis of human-rodent somatic cell hybrids and fluorescence in situ hybridization. The SREBF1 gene mapped to the proximal short arm of chromosome 17 (17p11.2), and the SREBF2 gene was localized to the long arm of chromosome 22 (22q13). 22 refs., 3 figs., 2 tabs.« less