3up3 › Citations

Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes.

Zhi X, Zhou XE, Melcher K, Motola DL, Gelmedin V, Hawdon J, Kliewer SA, Mangelsdorf DJ, Xu HE
J Biol Chem 287 4894-903 (2012)
Cited: 25 times
EuropePMC logo PMID: 22170062

Abstract

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.

Articles - 3up3 mentioned but not cited (4)

  1. Benchmarking of different molecular docking methods for protein-peptide docking. Agrawal P, Singh H, Srivastava HK, Singh S, Kishore G, Raghava GPS. BMC Bioinformatics 19 426 (2019)
  2. Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes. Zhi X, Zhou XE, Melcher K, Motola DL, Gelmedin V, Hawdon J, Kliewer SA, Mangelsdorf DJ, Xu HE. J Biol Chem 287 4894-4903 (2012)
  3. Using parallelized incremental meta-docking can solve the conformational sampling issue when docking large ligands to proteins. Devaurs D, Antunes DA, Hall-Swan S, Mitchell N, Moll M, Lizée G, Kavraki LE. BMC Mol Cell Biol 20 42 (2019)
  4. Mechanism of baixiangdan capsules on anti-neuroinflammation: combining dry and wet experiments. Yu Q, Liu M, Zhao T, Su M, Wang S, Xu W, He S, Li K, Mu X, Wu J, Sun P, Zheng F, Weng N. Aging (Albany NY) 15 7689-7708 (2023)


Reviews citing this publication (5)

  1. Interspecific communication between pinewood nematode, its insect vector, and associated microbes. Zhao L, Mota M, Vieira P, Butcher RA, Sun J. Trends Parasitol 30 299-308 (2014)
  2. Nuclear receptors: emerging drug targets for parasitic diseases. Wang Z, Schaffer NE, Kliewer SA, Mangelsdorf DJ. J Clin Invest 127 1165-1171 (2017)
  3. Natural products as chemical tools to dissect complex biology in C. elegans. Butcher RA. Curr Opin Chem Biol 50 138-144 (2019)
  4. On the role of dauer in the adaptation of nematodes to a parasitic lifestyle. Vlaar LE, Bertran A, Rahimi M, Dong L, Kammenga JE, Helder J, Goverse A, Bouwmeester HJ. Parasit Vectors 14 554 (2021)
  5. Helminth lipidomics: Technical aspects and future prospects. Wang T, Nie S, Reid GE, Gasser RB. Curr Res Parasitol Vector Borne Dis 1 100018 (2021)

Articles citing this publication (16)

  1. Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan. Mahanti P, Bose N, Bethke A, Judkins JC, Wollam J, Dumas KJ, Zimmerman AM, Campbell SL, Hu PJ, Antebi A, Schroeder FC. Cell Metab 19 73-83 (2014)
  2. Regulation of Life Cycle Checkpoints and Developmental Activation of Infective Larvae in Strongyloides stercoralis by Dafachronic Acid. Albarqi MM, Stoltzfus JD, Pilgrim AA, Nolan TJ, Wang Z, Kliewer SA, Mangelsdorf DJ, Lok JB. PLoS Pathog 12 e1005358 (2016)
  3. Small-molecule pheromones and hormones controlling nematode development. Butcher RA. Nat Chem Biol 13 577-586 (2017)
  4. Dafachronic acid promotes larval development in Haemonchus contortus by modulating dauer signalling and lipid metabolism. Ma G, Wang T, Korhonen PK, Young ND, Nie S, Ang CS, Williamson NA, Reid GE, Gasser RB. PLoS Pathog 15 e1007960 (2019)
  5. Expanding the view on the evolution of the nematode dauer signalling pathways: refinement through gene gain and pathway co-option. Gilabert A, Curran DM, Harvey SC, Wasmuth JD. BMC Genomics 17 476 (2016)
  6. C53: A novel particulate guanylyl cyclase B receptor activator that has sustained activity in vivo with anti-fibrotic actions in human cardiac and renal fibroblasts. Chen Y, Zheng Y, Iyer SR, Harders GE, Pan S, Chen HH, Ichiki T, Burnett JC, Sangaralingham SJ. J Mol Cell Cardiol 130 140-150 (2019)
  7. Structural insights into gene repression by the orphan nuclear receptor SHP. Zhi X, Zhou XE, He Y, Zechner C, Suino-Powell KM, Kliewer SA, Melcher K, Mangelsdorf DJ, Xu HE. Proc Natl Acad Sci U S A 111 839-844 (2014)
  8. Design, Synthesis, and Actions of an Innovative Bispecific Designer Peptide. Meems LMG, Andersen IA, Pan S, Harty G, Chen Y, Zheng Y, Harders GE, Ichiki T, Heublein DM, Iyer SR, Sangaralingham SJ, McCormick DJ, Burnett JC. Hypertension 73 900-909 (2019)
  9. Structural basis for corepressor assembly by the orphan nuclear receptor TLX. Zhi X, Zhou XE, He Y, Searose-Xu K, Zhang CL, Tsai CC, Melcher K, Xu HE. Genes Dev 29 440-450 (2015)
  10. New Insights into Orphan Nuclear Receptor SHP in Liver Cancer. Zou A, Lehn S, Magee N, Zhang Y. Nucl Receptor Res 2 101162 (2015)
  11. Signaling in Parasitic Nematodes: Physicochemical Communication Between Host and Parasite and Endogenous Molecular Transduction Pathways Governing Worm Development and Survival. Lok JB. Curr Clin Microbiol Rep 3 186-197 (2016)
  12. Dafachronic acid and temperature regulate canonical dauer pathways during Nippostrongylus brasiliensis infectious larvae activation. Ayoade KO, Carranza FR, Cho WH, Wang Z, Kliewer SA, Mangelsdorf DJ, Stoltzfus JDC. Parasit Vectors 13 162 (2020)
  13. The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12. Long T, Alberich M, André F, Menez C, Prichard RK, Lespine A. Sci Rep 10 11207 (2020)
  14. Caenorhabditis Intervention Testing Program: the farnesoid X receptor agonist obeticholic acid does not robustly extend lifespan in nematodes. Morshead ML, Sedore CA, Jones EG, Hall D, Plummer WT, Garrett T, Lucanic M, Guo M, Driscoll M, Phillips PC, Lithgow G. MicroPubl Biol 2020 (2020)
  15. Nuclear receptor nhr-48 is required for pathogenicity of the second stage (J2) of the plant parasite Meloidogyne incognita. Lu CJ, Tian BY, Cao Y, Zou CG, Zhang KQ. Sci Rep 6 34959 (2016)
  16. Expression profile of heat shock response factors during hookworm larval activation and parasitic development. Gelmedin V, Delaney A, Jennelle L, Hawdon JM. Mol Biochem Parasitol 202 1-14 (2015)


Quick links