Identification and inhibition of PIN1-NRF2 protein-protein interactions through computational and biophysical approaches

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dc.authoridOzleyen, Adem/0000-0003-0195-3383
dc.authoridDonmez, Serhat/0000-0002-6301-7243
dc.contributor.authorOzleyen, Adem
dc.contributor.authorDuran, Gizem Nur
dc.contributor.authorDonmez, Serhat
dc.contributor.authorOzbil, Mehmet
dc.contributor.authorDoveston, Richard G.
dc.contributor.authorTumer, Tugba Boyunegmez
dc.date.accessioned2025-05-29T02:57:49Z
dc.date.available2025-05-29T02:57:49Z
dc.date.issued2025
dc.departmentÇanakkale Onsekiz Mart Üniversitesi
dc.description.abstractNRF2 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 mu M. 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.
dc.description.sponsorshipMinistry of National Education of Republic of Turkiye within the scope of the YLSY scholarship program; COST Action [CA20121]; COST (European Cooperation in Science and Technology)
dc.description.sponsorshipThe authors would like to thank the Ministry of National Education of Republic of Turkiye 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.
dc.identifier.doi10.1038/s41598-025-89342-0
dc.identifier.issn2045-2322
dc.identifier.issue1
dc.identifier.pmid40087364
dc.identifier.scopus2-s2.0-105000116674
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1038/s41598-025-89342-0
dc.identifier.urihttps://hdl.handle.net/20.500.12428/30187
dc.identifier.volume15
dc.identifier.wosWOS:001445507400002
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherNature Portfolio
dc.relation.ispartofScientific Reports
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WOS_20250529
dc.subjectTranscription Factor Nrf2
dc.subjectWeb Server
dc.subjectBinding
dc.subjectRecognition
dc.subjectDomain
dc.subjectPeptide
dc.subjectActivation
dc.subjectParameters
dc.subjectMotifs
dc.subjectAcid
dc.titleIdentification and inhibition of PIN1-NRF2 protein-protein interactions through computational and biophysical approaches
dc.typeArticle

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