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

Xiaoyong Zhi, X. Edward Zhou, Karsten Melcher, Daniel L. Motola, Verena Gelmedin, John Hawdon, Steven A. Kliewer, David J. Mangelsdorf, H. Eric Xu

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4894-4903
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number7
DOIs
StatePublished - Feb 10 2012

Fingerprint

Bile Acids and Salts
Conservation
Ligands
Ancylostomatoidea
Parasites
Ancylostoma
Mammals
Caenorhabditis elegans
Cytoplasmic and Nuclear Receptors
Metabolites
Crystal structure
Chemical activation
X-Rays
Hormones
X rays
Molecules
cholestenoic acid
dafachronic acid
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Zhi, X., Zhou, X. E., Melcher, K., Motola, D. L., Gelmedin, V., Hawdon, J., ... Xu, H. E. (2012). Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes. Journal of Biological Chemistry, 287(7), 4894-4903. https://doi.org/10.1074/jbc.M111.315242

Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes. / Zhi, Xiaoyong; Zhou, X. Edward; Melcher, Karsten; Motola, Daniel L.; Gelmedin, Verena; Hawdon, John; Kliewer, Steven A.; Mangelsdorf, David J.; Xu, H. Eric.

In: Journal of Biological Chemistry, Vol. 287, No. 7, 10.02.2012, p. 4894-4903.

Research output: Contribution to journalArticle

Zhi, Xiaoyong ; Zhou, X. Edward ; Melcher, Karsten ; Motola, Daniel L. ; Gelmedin, Verena ; Hawdon, John ; Kliewer, Steven A. ; Mangelsdorf, David J. ; Xu, H. Eric. / Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 7. pp. 4894-4903.
@article{6267a50296924eca8518e00a81e5d7bc,
title = "Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes",
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.",
author = "Xiaoyong Zhi and Zhou, {X. Edward} and Karsten Melcher and Motola, {Daniel L.} and Verena Gelmedin and John Hawdon and Kliewer, {Steven A.} and Mangelsdorf, {David J.} and Xu, {H. Eric}",
year = "2012",
month = "2",
day = "10",
doi = "10.1074/jbc.M111.315242",
language = "English (US)",
volume = "287",
pages = "4894--4903",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "7",

}

TY - JOUR

T1 - Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes

AU - Zhi, Xiaoyong

AU - Zhou, X. Edward

AU - Melcher, Karsten

AU - Motola, Daniel L.

AU - Gelmedin, Verena

AU - Hawdon, John

AU - Kliewer, Steven A.

AU - Mangelsdorf, David J.

AU - Xu, H. Eric

PY - 2012/2/10

Y1 - 2012/2/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863143896&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863143896&partnerID=8YFLogxK

U2 - 10.1074/jbc.M111.315242

DO - 10.1074/jbc.M111.315242

M3 - Article

C2 - 22170062

AN - SCOPUS:84863143896

VL - 287

SP - 4894

EP - 4903

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 7

ER -