Low-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution.

PloS One
Amanda BernardesIgor Polikarpov

Abstract

The peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and carbohydrate metabolism, and are targets of drugs approved for human use. Whereas the crystallographic structure of the complex of full length PPARγ and RXRα is known, structural alterations induced by heterodimer formation and DNA contacts are not well understood. Herein, we report a small-angle X-ray scattering analysis of the oligomeric state of hPPARγ alone and in the presence of retinoid X receptor (RXR). The results reveal that, in contrast with other studied nuclear receptors, which predominantly form dimers in solution, hPPARγ remains in the monomeric form by itself but forms heterodimers with hRXRα. The low-resolution models of hPPARγ/RXRα complexes predict significant changes in opening angle between heterodimerization partners (LBD) and extended and asymmetric shape of the dimer (LBD-DBD) as compared with X-ray structure of the full-length receptor bound to DNA. These differences between our SAXS models and the high-resolution crystallographic structure might suggest that there are different conformations of functional heterodimer complex in solution. Accordingly, hydrogen/deuterium exchange experiments reveal that the hetero...Continue Reading

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Citations

Feb 25, 2014·Nature Structural & Molecular Biology·Xiaohua LouJan-Ake Gustafsson
Dec 2, 2014·Trends in Biochemical Sciences·Fraydoon RastinejadIgor Polikarpov
Nov 15, 2014·Analytical Chemistry·Gregory F PirroneJohn R Engen
Apr 22, 2015·Trends in Biochemical Sciences·Fraydoon RastinejadIgor Polikarpov
Apr 23, 2015·Trends in Biochemical Sciences·Dino MorasBruno P Klaholz
Jun 10, 2014·Molecular and Cellular Endocrinology·Jonathan A G MackinnonEva Estébanez-Perpiñá
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Jun 22, 2020·The Journal of Nutritional Biochemistry·Anaysa Paola BolinRosemari Otton
Jan 1, 2020·Current Research in Structural Biology·Steve TuskeEddy Arnold
Mar 14, 2021·Structure·Jinsai Shang, Douglas J Kojetin

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Methods Mentioned

BETA
protein crystallography
X-ray
size exclusion chromatography
electrophoresis
dynamic light scattering
gel
gel filtration

Software Mentioned

SAXS MoW
Dammin package
Gnom
Supcomb
Sasref
PyMOL
Masslinx
Fit2D
Gasbor packages
MS

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