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PDBsum entry 5u3v
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Protein binding/activator
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PDB id
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5u3v
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References listed in PDB file
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Key reference
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Title
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Structural basis for specific ligation of the peroxisome proliferator-Activated receptor δ.
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Authors
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C.C.Wu,
T.J.Baiga,
M.Downes,
J.J.La clair,
A.R.Atkins,
S.B.Richard,
W.Fan,
T.A.Stockley-Noel,
M.E.Bowman,
J.P.Noel,
R.M.Evans.
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Ref.
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Proc Natl Acad Sci U S A, 2017,
114,
E2563.
[DOI no: ]
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PubMed id
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Abstract
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The peroxisome proliferator-activated receptor (PPAR) family comprises three
subtypes: PPARα, PPARγ, and PPARδ. PPARδ transcriptionally modulates lipid
metabolism and the control of energy homeostasis; therefore, PPARδ agonists are
promising agents for treating a variety of metabolic disorders. In the present
study, we develop a panel of rationally designed PPARδ agonists. The modular
motif affords efficient syntheses using building blocks optimized for
interactions with subtype-specific residues in the PPARδ ligand-binding domain
(LBD). A combination of atomic-resolution protein X-ray crystallographic
structures, ligand-dependent LBD stabilization assays, and cell-based
transactivation measurements delineate structure-activity relationships (SARs)
for PPARδ-selective targeting and structural modulation. We identify key
ligand-induced conformational transitions of a conserved tryptophan side chain
in the LBD that trigger reorganization of the H2'-H3 surface segment of PPARδ.
The subtype-specific conservation of H2'-H3 sequences suggests that this
architectural remodeling constitutes a previously unrecognized conformational
switch accompanying ligand-dependent PPARδ transcriptional regulation.
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