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Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands.

Pochetti G, Godio C, Mitro N, Caruso D, Galmozzi A, Scurati S, Loiodice F, Fracchiolla G, Tortorella P, Laghezza A, Lavecchia A, Novellino E, Mazza F, Crestani M
J Biol Chem 282 17314-24 (2007)
Related entries: 1prg, 2i4j, 2i4p, 2prg, 4prg

Cited: 57 times
EuropePMC logo PMID: 17403688

Abstract

The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose and lipid metabolism. They are activated by natural ligands, such as fatty acids, and are also targets of synthetic antidiabetic and hypolipidemic drugs. By using cell-based reporter assays, we studied the transactivation activity of two enantiomeric ureidofibrate-like derivatives. In particular, we show that the R-enantiomer, (R)-1, is a full agonist of PPARgamma, whereas the S-enantiomer, (S)-1, is a less potent partial agonist. Most importantly, we report the x-ray crystal structures of the PPARgamma ligand binding domain complexed with the R- and the S-enantiomer, respectively. The analysis of the two crystal structures shows that the different degree of stabilization of the helix 12 induced by the ligand determines its behavior as full or partial agonist. Another crystal structure of the PPARgamma.(S)-1 complex, only differing in the soaking time of the ligand, is also presented. The comparison of the two structures of the complexes with the partial agonist reveals significant differences and is suggestive of the possible coexistence in solution of transcriptionally active and inactive forms of helix 12 in the presence of a partial agonist. Mutation analysis confirms the importance of Leu(465), Leu(469), and Ile(472) in the activation by (R)-1 and underscores the key role of Gln(286) in the PPARgamma activity.

Reviews - 2i4z mentioned but not cited (2)

  1. Review of the Structural and Dynamic Mechanisms of PPARγ Partial Agonism. Kroker AJ, Bruning JB. PPAR Res 2015 816856 (2015)
  2. Structural Biology-Based Exploration of Subtype-Selective Agonists for Peroxisome Proliferator-Activated Receptors. Miyachi H. Int J Mol Sci 22 9223 (2021)

Articles - 2i4z mentioned but not cited (3)

  1. Virtual Screening as a Technique for PPAR Modulator Discovery. Lewis SN, Bassaganya-Riera J, Bevan DR. PPAR Res 2010 861238 (2010)
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  3. A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability. Vasaturo M, Fiengo L, De Tommasi N, Sabatino L, Ziccardi P, Colantuoni V, Bruno M, Cerchia C, Novellino E, Lupo A, Lavecchia A, Piaz FD. Sci Rep 7 41273 (2017)


Reviews citing this publication (4)

  1. Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer's Disease. Govindarajulu M, Pinky PD, Bloemer J, Ghanei N, Suppiramaniam V, Amin R. PPAR Res 2018 2010675 (2018)
  2. Lysophospholipid interactions with protein targets. Parrill AL. Biochim Biophys Acta 1781 540-546 (2008)
  3. Nitro-fatty acids as novel electrophilic ligands for peroxisome proliferator-activated receptors. Ferreira AM, Minarrieta L, Lamas Bervejillo M, Rubbo H. Free Radic Biol Med 53 1654-1663 (2012)
  4. Identifying and characterizing promiscuous targets: implications for virtual screening. Pérez-Nueno VI, Ritchie DW. Expert Opin Drug Discov 7 1-17 (2012)

Articles citing this publication (48)

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