Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ

Zahra Heidari, Ian M. Chrisman, Michelle D. Nemetchek, Scott J. Novick, Anne-Laure Blayo, Trey Patton, Desiree E. Mendes, Philippe Diaz, Theodore M. Kamenecka, Patrick R. Griffin and Travis S. Hughes ()
Additional contact information
Zahra Heidari: University of Montana
Ian M. Chrisman: University of Montana
Michelle D. Nemetchek: University of Montana
Scott J. Novick: The Scripps Research Institute
Anne-Laure Blayo: The Scripps Research Institute
Trey Patton: University of Montana
Desiree E. Mendes: University of Montana
Philippe Diaz: University of Montana
Theodore M. Kamenecka: The Scripps Research Institute
Patrick R. Griffin: The Scripps Research Institute
Travis S. Hughes: University of Montana

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract The repressive states of nuclear receptors (i.e., apo or bound to antagonists or inverse agonists) are poorly defined, despite the fact that nuclear receptors are a major drug target. Most ligand bound structures of nuclear receptors, including peroxisome proliferator-activated receptor γ (PPARγ), are similar to the apo structure. Here we use NMR, accelerated molecular dynamics and hydrogen-deuterium exchange mass spectrometry to define the PPARγ structural ensemble. We find that the helix 3 charge clamp positioning varies widely in apo and is stabilized by efficacious ligand binding. We also reveal a previously undescribed mechanism for inverse agonism involving an omega loop to helix switch which induces disruption of a tripartite salt-bridge network. We demonstrate that ligand binding can induce multiple structurally distinct repressive states. One state recruits peptides from two different corepressors, while another recruits just one, providing structural evidence of ligand bias in a nuclear receptor.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-13768-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13768-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-13768-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().