5U3T

Human PPARdelta ligand-binding domain in complexed with specific agonist 4

Summary for 5U3T

• Entry DOI: 10.2210/pdb5u3t/pdb
• Descriptor: Peroxisome proliferator-activated receptor delta, 6-[2-({(propan-2-yl)[4-(thiophen-3-yl)benzene-1-carbonyl]amino}methyl)phenoxy]hexanoic acid, heptyl beta-D-glucopyranoside, ... (7 entities in total)
• Functional Keywords: ppardelta, ligand-binding domain, agonist, protein binding-activator complex, protein binding/activator
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 65340.22

Authors

Wu, C.-C.,Baiga, T.J.,Downes, M.,La Clair, J.J.,Atkins, A.R.,Richard, S.B.,Stockley-Noel, T.A.,Bowman, M.E.,Evans, R.M.,Noel, J.P. (deposition date: 2016-12-03, release date: 2017-03-22, Last modification date: 2024-10-09)

Primary citation

Wu, C.C.,Baiga, T.J.,Downes, M.,La Clair, J.J.,Atkins, A.R.,Richard, S.B.,Fan, W.,Stockley-Noel, T.A.,Bowman, M.E.,Noel, J.P.,Evans, R.M.
Structural basis for specific ligation of the peroxisome proliferator-activated receptor delta.
Proc. Natl. Acad. Sci. U.S.A., 114:E2563-E2570, 2017

PubMed Abstract: 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.

PubMed: 28320959
DOI: 10.1073/pnas.1621513114

Experimental method

X-RAY DIFFRACTION (1.7 Å)