Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism

Travis S. Hughes; Michael J. Chalmers; Scott Novick; Dana S. Kuruvilla; Mi Ra Chang; Theodore M. Kamenecka; Mark Rance; Bruce A. Johnson; Thomas P. Burris; Patrick R. Griffin; Douglas J. Kojetin

doi:10.1016/j.str.2011.10.018

Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism

Travis S. Hughes
, Michael J. Chalmers
, Scott Novick
, Dana S. Kuruvilla
, Mi Ra Chang
, Theodore M. Kamenecka
, Mark Rance
, Bruce A. Johnson
, Thomas P. Burris
, Patrick R. Griffin
, Douglas J. Kojetin

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

130 Scopus citations

Abstract

Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution nuclear magnetic resonance (NMR) studies that reveal peroxisome proliferator-activated receptor γ (PPARγ) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPARγ modulators.

Original language	English
Pages (from-to)	139-150
Number of pages	12
Journal	Structure
Volume	20
Issue number	1
DOIs	https://doi.org/10.1016/j.str.2011.10.018
State	Published - Jan 11 2012

Funding

We are grateful for support from B. Pascal and S. Willis for software analyzing the HDX data. This work was supported in part by James and Esther King Biomedical Research Program, Florida Department of Health (1KN-09 to D.J.K.), start-up funds from The Scripps Research Institute (to D.J.K.), the U.S. National Institutes of Health (NIH) National Institute of General Medical Sciences (R01-GM084041 to P.R.G.; R01-GM063855 to M.R.), and the National Center for Research Resources (RR19077 and RR027755 to M.R.).

Funders	Funder number
R01-GM063855, R01-GM084041
RR027755, S10RR019077
Florida Department of Health	1KN-09
Scripps Research Institute

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10.1016/j.str.2011.10.018

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title = "Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism",

abstract = "Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution nuclear magnetic resonance (NMR) studies that reveal peroxisome proliferator-activated receptor γ (PPARγ) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPARγ modulators.",

author = "Hughes, \{Travis S.\} and Chalmers, \{Michael J.\} and Scott Novick and Kuruvilla, \{Dana S.\} and Chang, \{Mi Ra\} and Kamenecka, \{Theodore M.\} and Mark Rance and Johnson, \{Bruce A.\} and Burris, \{Thomas P.\} and Griffin, \{Patrick R.\} and Kojetin, \{Douglas J.\}",

note = "Funding Information: We are grateful for support from B. Pascal and S. Willis for software analyzing the HDX data. This work was supported in part by James and Esther King Biomedical Research Program, Florida Department of Health (1KN-09 to D.J.K.), start-up funds from The Scripps Research Institute (to D.J.K.), the U.S. National Institutes of Health (NIH) National Institute of General Medical Sciences (R01-GM084041 to P.R.G.; R01-GM063855 to M.R.), and the National Center for Research Resources (RR19077 and RR027755 to M.R.). ",

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doi = "10.1016/j.str.2011.10.018",

language = "English",

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journal = "Structure",

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AU - Hughes, Travis S.

AU - Chalmers, Michael J.

AU - Novick, Scott

AU - Kuruvilla, Dana S.

AU - Chang, Mi Ra

AU - Kamenecka, Theodore M.

AU - Rance, Mark

AU - Johnson, Bruce A.

AU - Burris, Thomas P.

AU - Griffin, Patrick R.

AU - Kojetin, Douglas J.

N1 - Funding Information: We are grateful for support from B. Pascal and S. Willis for software analyzing the HDX data. This work was supported in part by James and Esther King Biomedical Research Program, Florida Department of Health (1KN-09 to D.J.K.), start-up funds from The Scripps Research Institute (to D.J.K.), the U.S. National Institutes of Health (NIH) National Institute of General Medical Sciences (R01-GM084041 to P.R.G.; R01-GM063855 to M.R.), and the National Center for Research Resources (RR19077 and RR027755 to M.R.).

PY - 2012/1/11

Y1 - 2012/1/11

N2 - Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution nuclear magnetic resonance (NMR) studies that reveal peroxisome proliferator-activated receptor γ (PPARγ) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPARγ modulators.

AB - Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution nuclear magnetic resonance (NMR) studies that reveal peroxisome proliferator-activated receptor γ (PPARγ) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPARγ modulators.

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DO - 10.1016/j.str.2011.10.018

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AN - SCOPUS:84855795379

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SP - 139

EP - 150

JO - Structure

JF - Structure

IS - 1

ER -

Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism

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