---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
_id: '19529'
abstract:
- lang: eng
text: NRF2 is a transcription factor responsible for coordinating the expression
of over a thousand cytoprotective genes. Although NRF2 is constitutively expressed,
its stability is modulated by the redox-sensitive protein KEAP1 and other conditional
binding partner regulators. The new era of NRF2 research has highlighted the cooperation
between NRF2 and PIN1 in modifying its cytoprotective effect. Despite numerous
studies, the understanding of the PIN1-NRF2 interaction remains limited. Herein,
we described the binding interaction of PIN1 and three different 14-mer long phospho-peptides
mimicking NRF2 protein using computer-based, biophysical, and biochemical approaches.
According to our computational analyses, the residues positioned in the WW domain
of PIN1 (Ser16, Arg17, Ser18, Tyr23, Ser32, Gln33, and Trp34) were found to be
crucial for PIN1-NRF2 interactions. Biophysical FP assays were used to verify
the computational prediction. The data demonstrated that Pintide, a peptide predominantly
interacting with the PIN1 WW-domain, led to a significant reduction in the binding
affinity of the NRF2 mimicking peptides. Moreover, we evaluated the impact of
known PIN1 inhibitors (juglone, KPT-6566, and EGCG) on the PIN1-NRF2 interaction.
Among the inhibitors, KPT-6566 showed the most potent inhibitory effect on PIN1-NRF2
interaction within an IC50 range of 0.3–1.4 µM. Furthermore,
our mass spectrometry analyses showed that KPT-6566 appeared to covalently modify
PIN1 via conjugate addition, rather than disulfide exchange of the sulfonyl-acetate
moiety. Altogether, such inhibitors would also be highly valuable molecular probes
for further investigation of PIN1 regulation of NRF2 in the cellular context and
potentially pave the way for drug molecules that specifically inhibit the cytoprotective
effects of NRF2 in cancer.
acknowledgement: The authors would like to thank the Ministry of National Education
of Republic of Türkiye within the scope of the YLSY scholarship program for funding
(AO). This article is based upon work from COST Action CA20121, supported by COST
(European Cooperation in Science and Technology) (www.cost.eu) (https://benbedphar.org/about-benbedphar/).
The molecular dynamics simulations reported in this paper were performed at TUBITAK
ULAKBIM, High Performance and Grid Computing Center (TRUBA resources). The authors
thank Dr Sharad Mistry for his support in acquiring and processing the MS data.
article_number: '8907'
article_processing_charge: Yes
article_type: original
author:
- first_name: Adem
full_name: Ozleyen, Adem
last_name: Ozleyen
- first_name: Gizem Nur
full_name: Duran, Gizem Nur
last_name: Duran
- first_name: Serhat
full_name: Dönmez, Serhat
id: 7c624079-3200-11ee-973b-9fcc8a575580
last_name: Dönmez
- first_name: Mehmet
full_name: Ozbil, Mehmet
last_name: Ozbil
- first_name: Richard G.
full_name: Doveston, Richard G.
last_name: Doveston
- first_name: Tugba Boyunegmez
full_name: Tumer, Tugba Boyunegmez
last_name: Tumer
citation:
ama: Ozleyen A, Duran GN, Dönmez S, Ozbil M, Doveston RG, Tumer TB. Identification
and inhibition of PIN1-NRF2 protein–protein interactions through computational
and biophysical approaches. Scientific Reports. 2025;15. doi:10.1038/s41598-025-89342-0
apa: Ozleyen, A., Duran, G. N., Dönmez, S., Ozbil, M., Doveston, R. G., & Tumer,
T. B. (2025). Identification and inhibition of PIN1-NRF2 protein–protein interactions
through computational and biophysical approaches. Scientific Reports. Springer
Nature. https://doi.org/10.1038/s41598-025-89342-0
chicago: Ozleyen, Adem, Gizem Nur Duran, Serhat Dönmez, Mehmet Ozbil, Richard G.
Doveston, and Tugba Boyunegmez Tumer. “Identification and Inhibition of PIN1-NRF2
Protein–Protein Interactions through Computational and Biophysical Approaches.”
Scientific Reports. Springer Nature, 2025. https://doi.org/10.1038/s41598-025-89342-0.
ieee: A. Ozleyen, G. N. Duran, S. Dönmez, M. Ozbil, R. G. Doveston, and T. B. Tumer,
“Identification and inhibition of PIN1-NRF2 protein–protein interactions through
computational and biophysical approaches,” Scientific Reports, vol. 15.
Springer Nature, 2025.
ista: Ozleyen A, Duran GN, Dönmez S, Ozbil M, Doveston RG, Tumer TB. 2025. Identification
and inhibition of PIN1-NRF2 protein–protein interactions through computational
and biophysical approaches. Scientific Reports. 15, 8907.
mla: Ozleyen, Adem, et al. “Identification and Inhibition of PIN1-NRF2 Protein–Protein
Interactions through Computational and Biophysical Approaches.” Scientific
Reports, vol. 15, 8907, Springer Nature, 2025, doi:10.1038/s41598-025-89342-0.
short: A. Ozleyen, G.N. Duran, S. Dönmez, M. Ozbil, R.G. Doveston, T.B. Tumer, Scientific
Reports 15 (2025).
date_created: 2025-04-08T11:12:20Z
date_published: 2025-03-14T00:00:00Z
date_updated: 2025-09-30T11:33:37Z
day: '14'
ddc:
- '570'
department:
- _id: LeSa
doi: 10.1038/s41598-025-89342-0
external_id:
isi:
- '001445507400002'
pmid:
- '40087364'
file:
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checksum: 6124a10402a67b66364cfa9350d35b4b
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creator: dernst
date_created: 2025-04-10T06:21:11Z
date_updated: 2025-04-10T06:21:11Z
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language:
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month: '03'
oa: 1
oa_version: Published Version
pmid: 1
publication: Scientific Reports
publication_identifier:
eissn:
- 2045-2322
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Identification and inhibition of PIN1-NRF2 protein–protein interactions through
computational and biophysical approaches
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345
volume: 15
year: '2025'
...