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PDBsum entry 5u3y
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Protein binding/activator
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PDB id
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5u3y
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PDB id:
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Protein binding/activator
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Title:
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Human ppardelta ligand-binding domain in complexed with specific agonist 9
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Structure:
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Peroxisome proliferator-activated receptor delta. Chain: a, b. Synonym: ppar-delta,nuci,nuclear hormone receptor 1,nuc1,nuclear receptor subfamily 1 group c member 2,peroxisome proliferator- activated receptor beta,ppar-beta. Engineered: yes. Other_details: ligand-binding domain
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ppard, nr1c2, pparb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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1.90Å
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R-factor:
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0.205
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R-free:
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0.246
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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, T.A.Stockley-Noel,M.E.Bowman,R.M.Evans,J.P.Noel
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Key ref:
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C.C.Wu
et al.
(2017).
Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ.
Proc Natl Acad Sci U S A,
114,
E2563.
PubMed id:
DOI:
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Date:
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03-Dec-16
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Release date:
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22-Mar-17
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PROCHECK
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Headers
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References
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Q03181
(PPARD_HUMAN) -
Peroxisome proliferator-activated receptor delta from Homo sapiens
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Seq:
Struc:
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441 a.a.
263 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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DOI no:
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Proc Natl Acad Sci U S A
114:E2563
(2017)
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PubMed id:
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Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ.
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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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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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