5U3X

Human PPARdelta ligand-binding domain in complexed with specific agonist 8

5U3X の概要

• エントリーDOI: 10.2210/pdb5u3x/pdb
• 関連するPDBエントリー: 5U3Q 5U3R 5U3S 5U3T 5U3U 5U3V 5U3W 5U3Y 5U3Z 5U40 5U41 5U42 5U44 5U45 5U46
• 分子名称: Peroxisome proliferator-activated receptor delta, 6-[2-({cyclopropyl[4-(pyridin-3-yl)benzene-1-carbonyl]amino}methyl)phenoxy]hexanoic acid, heptyl beta-D-glucopyranoside, ... (6 entities in total)
• 機能のキーワード: ppardelta, ligand-binding domain, agonist, protein binding-activator complex, protein binding/activator
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64400.97

構造登録者

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. (登録日: 2016-12-03, 公開日: 2017-03-22, 最終更新日: 2023-10-04)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)