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; Travis S. Hughes

doi:10.1038/s41467-019-13768-0

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
, Travis S. Hughes

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

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.

Original language	English
Article number	5825
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13768-0
State	Published - Dec 1 2019

Funding

NMR data presented herein were collected at the CUNY ASRC Biomolecular NMR Facility. We would like to thank Dr. James Aramini for his assistance in loading samples and troubleshooting technical problems. Writing assistance for this paper was provided by Shareen Grogan, Director of the University of Montana Writing and Public Speaking Center. Mass spectrometry of SR10221 was done by Eric Schultz at the UM CBSD Mass Spectrometry Core Facility. We also thank Dave Holley and the UM CBSD Molecular computation core facility for use of their computational resources. Funding for this work was provided by NIH grants R00DK103116 (T.S.H.), P20GM103546 (pilot project and J.I. grant to T.S.H.) and start-up funding provided by the University of Montana and P20GM103546 (T.S.H.). Molecular graphics and analyses performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311.

Funders	Funder number
P41-GM103311
P20GM103546
R00DK103116
University of California at San Francisco

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10.1038/s41467-019-13768-0

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title = "Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ",

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.",

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AU - Heidari, Zahra

AU - Chrisman, Ian M.

AU - Nemetchek, Michelle D.

AU - Novick, Scott J.

AU - Blayo, Anne Laure

AU - Patton, Trey

AU - Mendes, Desiree E.

AU - Diaz, Philippe

AU - Kamenecka, Theodore M.

AU - Griffin, Patrick R.

AU - Hughes, Travis S.

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AB - 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.

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

Abstract

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