Structural Conservation of Ligand Binding Reveals a Bile Acid-like Signaling Pathway in Nematodes
文献类型：期刊论文
| 作者 | Zhi, Xiaoyong1; Zhou, X. Edward1; Melcher, Karsten1,2; Motola, Daniel L.3; Gelmedin, Verena4; Hawdon, John4; Kliewer, Steven A.3,6; Mangelsdorf, David J.3,7; Xu, H. Eric1,5
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| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
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| 出版日期 | 2012-02-10 |
| 卷号 | 287期号:7页码:4894-4903 |
| ISSN号 | 0021-9258 |
| DOI | 10.1074/jbc.M111.315242 |
| 文献子类 | Article |
| 英文摘要 | Bile acid-like molecules named dafachronic acids (DAs) control the dauer formation program in Caenorhabditis elegans through the nuclear receptor DAF-12. This mechanism is conserved in parasitic nematodes to regulate their dauer-like infective larval stage, and as such, the DAF-12 ligand binding domain has been identified as an important therapeutic target in human parasitic hookworm species that infect more than 600 million people worldwide. Here, we report two x-ray crystal structures of the hookworm Ancylostoma ceylanicum DAF-12 ligand binding domain in complex with DA and cholestenoic acid (a bile acid-like metabolite), respectively. Structure analysis and functional studies reveal key residues responsible for species-specific ligand responses of DAF-12. Furthermore, DA binds to DAF-12 mechanistically and is structurally similar to bile acids binding to the mammalian bile acid receptor farnesoid X receptor. Activation of DAF-12 by cholestenoic acid and the cholestenoic acid complex structure suggest that bile acid-like signaling pathways have been conserved in nematodes and mammals. Together, these results reveal the molecular mechanism for the interplay between parasite and host, provide a structural framework for DAF-12 as a promising target in treating nematode parasitism, and provide insight into the evolution of gut parasite hormone-signaling pathways. |
| WOS关键词 | ELEGANS DAUER FORMATION ; NUCLEAR RECEPTOR ; C-ELEGANS ; CRYSTAL-STRUCTURE ; DAF-12 ; IDENTIFICATION ; ACTIVATION ; LONGEVITY ; OXYGENASE ; DISEASE |
| 资助项目 | National Institutes of Health[DK071662] ; National Institutes of Health[DK066202] ; National Institutes of Health[HL089301] ; National Institutes of Health[DK62434] ; Jay and Betty Van Andel Foundation[00000000] ; Howard Hughes Medical Institute[00000000] ; Robert A. Welch Foundation[I-1275] ; Robert A. Welch Foundation[I-1558] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000300608500050 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278183]  |
| 专题 | 药物靶标结构与功能中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Xu, H. Eric |
| 作者单位 | 1.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA; 2.Van Andel Res Inst, Lab Struct Biol & Biochem, Grand Rapids, MI 49503 USA; 3.Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA; 4.George Washington Univ, Med Ctr, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, VARI SIMM Ctr,State Key Lab Drug Res, Shanghai 201203, Peoples R China; 6.Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA; 7.Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA |
| 推荐引用方式 GB/T 7714 | Zhi, Xiaoyong,Zhou, X. Edward,Melcher, Karsten,et al. Structural Conservation of Ligand Binding Reveals a Bile Acid-like Signaling Pathway in Nematodes[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2012,287(7):4894-4903. |
| APA | Zhi, Xiaoyong.,Zhou, X. Edward.,Melcher, Karsten.,Motola, Daniel L..,Gelmedin, Verena.,...&Xu, H. Eric.(2012).Structural Conservation of Ligand Binding Reveals a Bile Acid-like Signaling Pathway in Nematodes.JOURNAL OF BIOLOGICAL CHEMISTRY,287(7),4894-4903. |
| MLA | Zhi, Xiaoyong,et al."Structural Conservation of Ligand Binding Reveals a Bile Acid-like Signaling Pathway in Nematodes".JOURNAL OF BIOLOGICAL CHEMISTRY 287.7(2012):4894-4903. |
入库方式： OAI收割
来源：上海药物研究所
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