Bidirectional fluorescence properties of pyrene-based peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist

Shintaro Ban, Takuji Oyama, Jun Ichi Kasuga, Kenji Ohgane, Yoshino Nishio, Kosuke Morikawa, Yuichi Hashimoto, Hiroyuki Miyachi

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Based on X-ray crystallographic analysis of a peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist complexed with human PPARs ligand binding domain (LBD), we previously reported the design and synthesis of a pyrene-based fluorescent PPARα/δ co-agonist 2. Here, we found that the fluorescence intensity of 2 increased upon binding to hPPARα-LBD, in a manner dependent upon the concentration of the LBD. But, surprisingly, the fluorescence intensity of 2 decreased concentration- dependently upon binding to hPPRδ-LBD. Site-directed mutagenesis of the two hPPAR subtypes clearly indicated that Trp264 of hPPARδ-LBD, located between H2′ helix and H3 helix (omega loop), is critical for the concentration-dependent decrease in fluorescence intensity, which is suggested to be due to fluorescence resonance energy transfer (FRET) from the pyrene moiety of bound 2 to the nearby side-chain indole moiety of Trp264 in the hPPARδ-LBD.

Original languageEnglish
Pages (from-to)3460-3464
Number of pages5
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number11
DOIs
Publication statusPublished - Jun 1 2012

Fingerprint

Peroxisome Proliferator-Activated Receptors
Fluorescence
Ligands
Mutagenesis
Fluorescence Resonance Energy Transfer
Site-Directed Mutagenesis
pyrene
X-Rays
X rays

Keywords

  • Fluorescent PPARα/δ co-agonist
  • Peroxisome proliferator-activated receptor
  • PPARα
  • PPARδ
  • Site-directed mutagenesis

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Bidirectional fluorescence properties of pyrene-based peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist. / Ban, Shintaro; Oyama, Takuji; Kasuga, Jun Ichi; Ohgane, Kenji; Nishio, Yoshino; Morikawa, Kosuke; Hashimoto, Yuichi; Miyachi, Hiroyuki.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 11, 01.06.2012, p. 3460-3464.

Research output: Contribution to journalArticle

Ban, S, Oyama, T, Kasuga, JI, Ohgane, K, Nishio, Y, Morikawa, K, Hashimoto, Y & Miyachi, H 2012, 'Bidirectional fluorescence properties of pyrene-based peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist', Bioorganic and Medicinal Chemistry, vol. 20, no. 11, pp. 3460-3464. https://doi.org/10.1016/j.bmc.2012.04.015
Ban, Shintaro ; Oyama, Takuji ; Kasuga, Jun Ichi ; Ohgane, Kenji ; Nishio, Yoshino ; Morikawa, Kosuke ; Hashimoto, Yuichi ; Miyachi, Hiroyuki. / Bidirectional fluorescence properties of pyrene-based peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 11. pp. 3460-3464.
@article{55729d6b5d87404c825db5c07e3540e8,
title = "Bidirectional fluorescence properties of pyrene-based peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist",
abstract = "Based on X-ray crystallographic analysis of a peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist complexed with human PPARs ligand binding domain (LBD), we previously reported the design and synthesis of a pyrene-based fluorescent PPARα/δ co-agonist 2. Here, we found that the fluorescence intensity of 2 increased upon binding to hPPARα-LBD, in a manner dependent upon the concentration of the LBD. But, surprisingly, the fluorescence intensity of 2 decreased concentration- dependently upon binding to hPPRδ-LBD. Site-directed mutagenesis of the two hPPAR subtypes clearly indicated that Trp264 of hPPARδ-LBD, located between H2′ helix and H3 helix (omega loop), is critical for the concentration-dependent decrease in fluorescence intensity, which is suggested to be due to fluorescence resonance energy transfer (FRET) from the pyrene moiety of bound 2 to the nearby side-chain indole moiety of Trp264 in the hPPARδ-LBD.",
keywords = "Fluorescent PPARα/δ co-agonist, Peroxisome proliferator-activated receptor, PPARα, PPARδ, Site-directed mutagenesis",
author = "Shintaro Ban and Takuji Oyama and Kasuga, {Jun Ichi} and Kenji Ohgane and Yoshino Nishio and Kosuke Morikawa and Yuichi Hashimoto and Hiroyuki Miyachi",
year = "2012",
month = "6",
day = "1",
doi = "10.1016/j.bmc.2012.04.015",
language = "English",
volume = "20",
pages = "3460--3464",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "11",

}

TY - JOUR

T1 - Bidirectional fluorescence properties of pyrene-based peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist

AU - Ban, Shintaro

AU - Oyama, Takuji

AU - Kasuga, Jun Ichi

AU - Ohgane, Kenji

AU - Nishio, Yoshino

AU - Morikawa, Kosuke

AU - Hashimoto, Yuichi

AU - Miyachi, Hiroyuki

PY - 2012/6/1

Y1 - 2012/6/1

N2 - Based on X-ray crystallographic analysis of a peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist complexed with human PPARs ligand binding domain (LBD), we previously reported the design and synthesis of a pyrene-based fluorescent PPARα/δ co-agonist 2. Here, we found that the fluorescence intensity of 2 increased upon binding to hPPARα-LBD, in a manner dependent upon the concentration of the LBD. But, surprisingly, the fluorescence intensity of 2 decreased concentration- dependently upon binding to hPPRδ-LBD. Site-directed mutagenesis of the two hPPAR subtypes clearly indicated that Trp264 of hPPARδ-LBD, located between H2′ helix and H3 helix (omega loop), is critical for the concentration-dependent decrease in fluorescence intensity, which is suggested to be due to fluorescence resonance energy transfer (FRET) from the pyrene moiety of bound 2 to the nearby side-chain indole moiety of Trp264 in the hPPARδ-LBD.

AB - Based on X-ray crystallographic analysis of a peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist complexed with human PPARs ligand binding domain (LBD), we previously reported the design and synthesis of a pyrene-based fluorescent PPARα/δ co-agonist 2. Here, we found that the fluorescence intensity of 2 increased upon binding to hPPARα-LBD, in a manner dependent upon the concentration of the LBD. But, surprisingly, the fluorescence intensity of 2 decreased concentration- dependently upon binding to hPPRδ-LBD. Site-directed mutagenesis of the two hPPAR subtypes clearly indicated that Trp264 of hPPARδ-LBD, located between H2′ helix and H3 helix (omega loop), is critical for the concentration-dependent decrease in fluorescence intensity, which is suggested to be due to fluorescence resonance energy transfer (FRET) from the pyrene moiety of bound 2 to the nearby side-chain indole moiety of Trp264 in the hPPARδ-LBD.

KW - Fluorescent PPARα/δ co-agonist

KW - Peroxisome proliferator-activated receptor

KW - PPARα

KW - PPARδ

KW - Site-directed mutagenesis

UR - http://www.scopus.com/inward/record.url?scp=84861188794&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861188794&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2012.04.015

DO - 10.1016/j.bmc.2012.04.015

M3 - Article

VL - 20

SP - 3460

EP - 3464

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 11

ER -