A structural mechanism for directing corepressor-selective inverse agonism of PPARγ

Richard Brust; Jinsai Shang; Jakob Fuhrmann; Sarah A. Mosure; Jared Bass; Andrew Cano; Zahra Heidari; Ian M. Chrisman; Michelle D. Nemetchek; Anne-Laure Blayo; Patrick R. Griffin; Theodore M. Kamenecka; Travis S. Hughes; Douglas J. Kojetin

doi:10.1038/s41467-018-07133-w

Nature Communications (Nov 2018)

A structural mechanism for directing corepressor-selective inverse agonism of PPARγ

Richard Brust,
Jinsai Shang,
Jakob Fuhrmann,
Sarah A. Mosure,
Jared Bass,
Andrew Cano,
Zahra Heidari,
Ian M. Chrisman,
Michelle D. Nemetchek,
Anne-Laure Blayo,
Patrick R. Griffin,
Theodore M. Kamenecka,
Travis S. Hughes,
Douglas J. Kojetin

Affiliations

Richard Brust: Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Jinsai Shang: Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Jakob Fuhrmann: Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Sarah A. Mosure: Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Jared Bass: Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Andrew Cano: Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Zahra Heidari: Department of Biomedical and Pharmaceutical Sciences, University of Montana
Ian M. Chrisman: Center for Biomolecular Structure and Dynamics, University of Montana
Michelle D. Nemetchek: Center for Biomolecular Structure and Dynamics, University of Montana
Anne-Laure Blayo: Department of Molecular Medicine, The Scripps Research Institute
Patrick R. Griffin: Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Theodore M. Kamenecka: Department of Molecular Medicine, The Scripps Research Institute
Travis S. Hughes: Department of Biomedical and Pharmaceutical Sciences, University of Montana
Douglas J. Kojetin: Department of Integrative Structural and Computational Biology, The Scripps Research Institute

DOI: https://doi.org/10.1038/s41467-018-07133-w
Journal volume & issue: Vol. 9, no. 1
pp. 1 – 14

Abstract

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Peroxisome proliferator-activated receptor gamma (PPARγ) is a target for insulin sensitizing drugs. Here the authors combine NMR, X-ray crystallography and MD simulations and report a structural mechanism for eliciting PPARγ inverse agonism, where coactivator binding is inhibited and corepressor binding promoted, which causes PPARγ repression.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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