1Y0S

Crystal structure of PPAR delta complexed with GW2331

Summary for 1Y0S

• Entry DOI: 10.2210/pdb1y0s/pdb
• Descriptor: Peroxisome proliferator activated receptor delta, IODIDE ION, (2S)-2-(4-[2-(3-[2,4-DIFLUOROPHENYL]-1-HEPTYLUREIDO)ETHYL]PHENOXY)-2-METHYLBUTYRIC ACID, ... (5 entities in total)
• Functional Keywords: ppar, hormone-growth factor receptor complex, hormone/growth factor receptor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 65162.15

Authors

Takada, I.,Yu, R.T.,Xu, H.E.,Xu, R.X.,Lambert, M.H.,Montana, V.G.,Kliewer, S.A.,Evans, R.M.,Umesono, K. (deposition date: 2004-11-16, release date: 2005-03-29, Last modification date: 2023-08-23)

Primary citation

Takada, I.,Yu, R.T.,Xu, H.E.,Lambert, M.H.,Montana, V.G.,Kliewer, S.A.,Evans, R.M.,Umesono, K.
Alteration of a Single Amino Acid in Peroxisome Proliferator-Activated Receptor-alpha (PPARalpha) Generates a PPAR delta Phenotype
MOL.ENDOCRINOL., 14:733-740, 2000

PubMed Abstract: Three pharmacologically important nuclear receptors, the peroxisome proliferator-activated receptors (PPARs alpha, gamma, and delta), mediate key transcriptional responses involved in lipid homeostasis. The PPAR alpha and gamma subtypes are well conserved from Xenopus to man, but the beta/delta subtypes display substantial species variations in both structure and ligand activation profiles. Characterization of the avian cognates revealed a close relationship between chick (c) alpha and gamma subtypes to their mammalian counterparts, whereas the third chicken subtype was intermediate to Xenopus (x) beta and mammalian delta, establishing that beta and delta are orthologs. Like xPPAR beta, cPPAR beta responded efficiently to hypolipidemic compounds that fail to activate the human counterpart. This provided the opportunity to address the pharmacological problem as to how drug selectivity is achieved and the more global evolutionary question as to the minimal changes needed to generate a new class of receptor. X-ray crystallography and chimeric analyses combined with site-directed mutagenesis of avian and mammalian cognates revealed that a Met to Val change at residue 417 was sufficient to switch the human and chick phenotype. These results establish that the genetic drive to evolve a novel and functionally selectable receptor can be modulated by a single amino acid change and suggest how nuclear receptors can accommodate natural variation in species physiology.

PubMed: 10809235
DOI: 10.1210/me.14.5.733

Experimental method

X-RAY DIFFRACTION (2.65 Å)