Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form
As of April 1st VIVO Scientific Profiles will no longer updated for faculty, and the link to VIVO will be removed from the library website. Faculty profile pages will continue to be updated via Interfolio. VIVO will continue being used behind the scenes to update graduate student profiles. Please contact helplib@scripps.edu if you have questions.
How to download citations from VIVO | Alternative profile options

Partial agonists activate PPAR gamma using a helix 12 independent mechanism

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Bruning, John
  • Chalmers, Michael
  • Prasad, S.
  • Busby, S. A.
  • Kamenecka, Theodore
  • He, Y.
  • Nettles, Kendall
  • Griffin, Patrick

publication date

  • October 2007

journal

  • Structure  Journal

abstract

  • Binding to helix 12 of the ligand-binding domain of PPARgamma is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPARgamma with agonists that induced graded transcriptional responses. Here we present crystal structures and amide H/D exchange (HDX) kinetics for six of these complexes. Amide HDX revealed each ligand induced unique changes to the dynamics of the ligand-binding domain (LBD). Full agonists stabilized helix 12, whereas intermediate and partial agonists did not at all, and rather differentially stabilized other regions of the binding pocket. The gradient of PPARgamma transactivation cannot be accounted for solely through changes to the dynamics of AF-2. Thus, our understanding of allosteric signaling must be extended beyond the idea of a dynamic helix 12 acting as a molecular switch.

subject areas

  • Animals
  • Binding Sites
  • COS Cells
  • Cercopithecus aethiops
  • Deuterium Exchange Measurement
  • Ligands
  • Models, Molecular
  • PPAR gamma
  • Protein Structure, Tertiary
scroll to property group menus

Identity

International Standard Serial Number (ISSN)

  • 0969-2126

Digital Object Identifier (DOI)

  • 10.1016/j.str.2007.07.014

PubMed ID

  • 17937915
scroll to property group menus

Additional Document Info

start page

  • 1258

end page

  • 1271

volume

  • 15

issue

  • 10

©2022 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support