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Structural and functional profiling of environmental ligands for estrogen receptors.

Delfosse V, Grimaldi M, Cavaillès V, Balaguer P, Bourguet W - Environ. Health Perspect. (2014)

Bottom Line: However, most of these compounds are chemically unrelated to natural hormones, so their binding modes and associated hormonal activities are hardly predictable.We observed xenoestrogens binding to both ERs-with affinities ranging from subnanomolar to micromolar values-and acting in a subtype-dependent fashion as full agonists or partial agonists/antagonists by using different combinations of the activation functions 1 and 2 of ERα and ERβ.The precise characterization of the interactions between major environmental pollutants and two of their primary biological targets provides rational guidelines for the design of safer chemicals, and will increase the accuracy and usefulness of structure-based computational methods, allowing for activity prediction of chemicals in risk assessment.

View Article: PubMed Central - PubMed

Affiliation: Inserm (Institut national de la santé et de la recherche médicale) U1054, Montpellier, France.

ABSTRACT

Background: Individuals are exposed daily to environmental pollutants that may act as endocrine-disrupting chemicals (EDCs), causing a range of developmental, reproductive, metabolic, or neoplastic diseases. With their mostly hydrophobic pocket that serves as a docking site for endogenous and exogenous ligands, nuclear receptors (NRs) can be primary targets of small molecule environmental contaminants. However, most of these compounds are chemically unrelated to natural hormones, so their binding modes and associated hormonal activities are hardly predictable.

Objectives: We conducted a correlative analysis of structural and functional data to gain insight into the mechanisms by which 12 members of representative families of pollutants bind to and activate the estrogen receptors ERα and ERβ.

Methods: We used a battery of biochemical, structural, biophysical, and cell-based approaches to characterize the interaction between ERs and their environmental ligands.

Results: Our study revealed that the chemically diverse compounds bound to ERs via varied sets of protein-ligand interactions, reflecting their differential activities, binding affinities, and specificities. We observed xenoestrogens binding to both ERs-with affinities ranging from subnanomolar to micromolar values-and acting in a subtype-dependent fashion as full agonists or partial agonists/antagonists by using different combinations of the activation functions 1 and 2 of ERα and ERβ.

Conclusions: The precise characterization of the interactions between major environmental pollutants and two of their primary biological targets provides rational guidelines for the design of safer chemicals, and will increase the accuracy and usefulness of structure-based computational methods, allowing for activity prediction of chemicals in risk assessment.

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Related in: MedlinePlus

Methionine 421 confers plasticity and adaptability to ERα LBP. Structure superposition of E2-bound ERβ LBD (yellow) with (A) ferutinine-bound ERα LBD (green), or (B) BBP-bound ERα LBD (gray). The presence of I373 in ERβ instead of M421 in ERα will induce a shift of bulky ligands toward helix H12 thus lowering the stability of the AF‑2.
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f5: Methionine 421 confers plasticity and adaptability to ERα LBP. Structure superposition of E2-bound ERβ LBD (yellow) with (A) ferutinine-bound ERα LBD (green), or (B) BBP-bound ERα LBD (gray). The presence of I373 in ERβ instead of M421 in ERα will induce a shift of bulky ligands toward helix H12 thus lowering the stability of the AF‑2.

Mentions: Accordingly, our structures reveal that most of the compounds insert a bulky feature in this region of the LBP and exhibit a marked subtype-dependent activity as illustrated by ferutinine and BBP (Figures 5 and 3B). Both molecules contain a bulky group that projects toward ERα M421, which, in turn, must undergo a large conformational change. In ERβ, the linear amino acid M421 is replaced by the branched residue I373, which is unable to move away from the pocket and make room for the ligands. A likely consequence is that I373 induces a shift of the ligands toward H12, thus lowering the interaction of H12 in the active conformation with the LBD surface and accounting for the weakest agonistic activity of the compounds in ERβ (Figure 5). Obviously the strength of the steric constraints applied to ERβ H12 varies according to the chemical structure of the bound ligand, as reflected by the graded partial agonistic/antagonistic activity of the compounds (Figure 3B). Finally, it is noteworthy that the weak ligand-induced ERβ AF-2 activity can be partially or completely compensated by the N-terminal activation domain, thus confirming the preeminent functional role of ERβ AF-1 in HeLa cells (Figure 3A,B).


Structural and functional profiling of environmental ligands for estrogen receptors.

Delfosse V, Grimaldi M, Cavaillès V, Balaguer P, Bourguet W - Environ. Health Perspect. (2014)

Methionine 421 confers plasticity and adaptability to ERα LBP. Structure superposition of E2-bound ERβ LBD (yellow) with (A) ferutinine-bound ERα LBD (green), or (B) BBP-bound ERα LBD (gray). The presence of I373 in ERβ instead of M421 in ERα will induce a shift of bulky ligands toward helix H12 thus lowering the stability of the AF‑2.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256047&req=5

f5: Methionine 421 confers plasticity and adaptability to ERα LBP. Structure superposition of E2-bound ERβ LBD (yellow) with (A) ferutinine-bound ERα LBD (green), or (B) BBP-bound ERα LBD (gray). The presence of I373 in ERβ instead of M421 in ERα will induce a shift of bulky ligands toward helix H12 thus lowering the stability of the AF‑2.
Mentions: Accordingly, our structures reveal that most of the compounds insert a bulky feature in this region of the LBP and exhibit a marked subtype-dependent activity as illustrated by ferutinine and BBP (Figures 5 and 3B). Both molecules contain a bulky group that projects toward ERα M421, which, in turn, must undergo a large conformational change. In ERβ, the linear amino acid M421 is replaced by the branched residue I373, which is unable to move away from the pocket and make room for the ligands. A likely consequence is that I373 induces a shift of the ligands toward H12, thus lowering the interaction of H12 in the active conformation with the LBD surface and accounting for the weakest agonistic activity of the compounds in ERβ (Figure 5). Obviously the strength of the steric constraints applied to ERβ H12 varies according to the chemical structure of the bound ligand, as reflected by the graded partial agonistic/antagonistic activity of the compounds (Figure 3B). Finally, it is noteworthy that the weak ligand-induced ERβ AF-2 activity can be partially or completely compensated by the N-terminal activation domain, thus confirming the preeminent functional role of ERβ AF-1 in HeLa cells (Figure 3A,B).

Bottom Line: However, most of these compounds are chemically unrelated to natural hormones, so their binding modes and associated hormonal activities are hardly predictable.We observed xenoestrogens binding to both ERs-with affinities ranging from subnanomolar to micromolar values-and acting in a subtype-dependent fashion as full agonists or partial agonists/antagonists by using different combinations of the activation functions 1 and 2 of ERα and ERβ.The precise characterization of the interactions between major environmental pollutants and two of their primary biological targets provides rational guidelines for the design of safer chemicals, and will increase the accuracy and usefulness of structure-based computational methods, allowing for activity prediction of chemicals in risk assessment.

View Article: PubMed Central - PubMed

Affiliation: Inserm (Institut national de la santé et de la recherche médicale) U1054, Montpellier, France.

ABSTRACT

Background: Individuals are exposed daily to environmental pollutants that may act as endocrine-disrupting chemicals (EDCs), causing a range of developmental, reproductive, metabolic, or neoplastic diseases. With their mostly hydrophobic pocket that serves as a docking site for endogenous and exogenous ligands, nuclear receptors (NRs) can be primary targets of small molecule environmental contaminants. However, most of these compounds are chemically unrelated to natural hormones, so their binding modes and associated hormonal activities are hardly predictable.

Objectives: We conducted a correlative analysis of structural and functional data to gain insight into the mechanisms by which 12 members of representative families of pollutants bind to and activate the estrogen receptors ERα and ERβ.

Methods: We used a battery of biochemical, structural, biophysical, and cell-based approaches to characterize the interaction between ERs and their environmental ligands.

Results: Our study revealed that the chemically diverse compounds bound to ERs via varied sets of protein-ligand interactions, reflecting their differential activities, binding affinities, and specificities. We observed xenoestrogens binding to both ERs-with affinities ranging from subnanomolar to micromolar values-and acting in a subtype-dependent fashion as full agonists or partial agonists/antagonists by using different combinations of the activation functions 1 and 2 of ERα and ERβ.

Conclusions: The precise characterization of the interactions between major environmental pollutants and two of their primary biological targets provides rational guidelines for the design of safer chemicals, and will increase the accuracy and usefulness of structure-based computational methods, allowing for activity prediction of chemicals in risk assessment.

Show MeSH
Related in: MedlinePlus