Molecular recognition of fatty acids by peroxisome proliferator- activated receptors

H. Eric Xu; Millard H. Lambert; Valerie G. Montana; Derek J. Parks; Steven G. Blanchard; Peter J. Brown; Daniel D. Sternbach; Jürgen M. Lehmann; G. Bruce Wisely; Timothy M. Willson; Steven A. Kliewer; Michael V. Milburn

doi:10.1016/S1097-2765(00)80467-0

Molecular recognition of fatty acids by peroxisome proliferator- activated receptors

H. Eric Xu, Millard H. Lambert, Valerie G. Montana, Derek J. Parks, Steven G. Blanchard, Peter J. Brown, Daniel D. Sternbach, Jürgen M. Lehmann, G. Bruce Wisely, Timothy M. Willson, Steven A. Kliewer, Michael V. Milburn

Research output: Contribution to journal › Article › peer-review

985 Scopus citations

Abstract

The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for fatty acids (FAs) that regulate glucose and lipid homeostasis. We report the crystal structure of the PPARδ ligand-binding domain (LBD) bound to either the FA eicosapentaenoic acid (EPA) or the synthetic fib rate GW2433. The carboxylic acids of EPA and GW2433 interact directly with the activation function 2 (AF-2) helix. The hydrophobic tail of EPA adopts two distinct conformations within the large hydrophobic cavity. GW2433 occupies essentially the same space as EPA bound in both conformations. These structures provide molecular insight into the propensity for PPARs to interact with a variety of synthetic and natural compounds, including FAs that vary in both chain length and degree of saturation.

Original language	English (US)
Pages (from-to)	397-403
Number of pages	7
Journal	Molecular cell
Volume	3
Issue number	3
DOIs	https://doi.org/10.1016/S1097-2765(00)80467-0
State	Published - Mar 1999

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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title = "Molecular recognition of fatty acids by peroxisome proliferator- activated receptors",

abstract = "The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for fatty acids (FAs) that regulate glucose and lipid homeostasis. We report the crystal structure of the PPARδ ligand-binding domain (LBD) bound to either the FA eicosapentaenoic acid (EPA) or the synthetic fib rate GW2433. The carboxylic acids of EPA and GW2433 interact directly with the activation function 2 (AF-2) helix. The hydrophobic tail of EPA adopts two distinct conformations within the large hydrophobic cavity. GW2433 occupies essentially the same space as EPA bound in both conformations. These structures provide molecular insight into the propensity for PPARs to interact with a variety of synthetic and natural compounds, including FAs that vary in both chain length and degree of saturation.",

author = "Xu, {H. Eric} and Lambert, {Millard H.} and Montana, {Valerie G.} and Parks, {Derek J.} and Blanchard, {Steven G.} and Brown, {Peter J.} and Sternbach, {Daniel D.} and Lehmann, {J{\"u}rgen M.} and Wisely, {G. Bruce} and Willson, {Timothy M.} and Kliewer, {Steven A.} and Milburn, {Michael V.}",

year = "1999",

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T1 - Molecular recognition of fatty acids by peroxisome proliferator- activated receptors

AU - Xu, H. Eric

AU - Lambert, Millard H.

AU - Montana, Valerie G.

AU - Parks, Derek J.

AU - Blanchard, Steven G.

AU - Brown, Peter J.

AU - Sternbach, Daniel D.

AU - Lehmann, Jürgen M.

AU - Wisely, G. Bruce

AU - Willson, Timothy M.

AU - Kliewer, Steven A.

AU - Milburn, Michael V.

PY - 1999/3

Y1 - 1999/3

N2 - The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for fatty acids (FAs) that regulate glucose and lipid homeostasis. We report the crystal structure of the PPARδ ligand-binding domain (LBD) bound to either the FA eicosapentaenoic acid (EPA) or the synthetic fib rate GW2433. The carboxylic acids of EPA and GW2433 interact directly with the activation function 2 (AF-2) helix. The hydrophobic tail of EPA adopts two distinct conformations within the large hydrophobic cavity. GW2433 occupies essentially the same space as EPA bound in both conformations. These structures provide molecular insight into the propensity for PPARs to interact with a variety of synthetic and natural compounds, including FAs that vary in both chain length and degree of saturation.

AB - The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for fatty acids (FAs) that regulate glucose and lipid homeostasis. We report the crystal structure of the PPARδ ligand-binding domain (LBD) bound to either the FA eicosapentaenoic acid (EPA) or the synthetic fib rate GW2433. The carboxylic acids of EPA and GW2433 interact directly with the activation function 2 (AF-2) helix. The hydrophobic tail of EPA adopts two distinct conformations within the large hydrophobic cavity. GW2433 occupies essentially the same space as EPA bound in both conformations. These structures provide molecular insight into the propensity for PPARs to interact with a variety of synthetic and natural compounds, including FAs that vary in both chain length and degree of saturation.

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Molecular recognition of fatty acids by peroxisome proliferator- activated receptors

Abstract

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