Inhibition of mutant RAS-RAF interaction by mimicking structural and dynamic properties of phosphorylated RAS

Basit Öğe Kaydı
dc.contributor.authorİlter, Metehan
dc.contributor.authorKaşmer, Ramazan
dc.contributor.authorJalalypour, Farzaneh
dc.contributor.authorAtılgan, Canan
dc.contributor.authorTopçu, Ozan
dc.contributor.authorKarakaş, Nihal
dc.contributor.authorŞensoy, Özge
dc.date.accessioned2023-01-09T06:48:07Z
dc.date.available2023-01-09T06:48:07Z
dc.date.issued2022
dc.departmentİstanbul Medipol Üniversitesi, Sağlık Bilimleri Enstitüsü, Tıbbi Biyoloji ve Genetik Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Bilgisayar Mühendisliği Bölümü
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.description.abstractUndruggability of RAS proteins has necessitated alternative strategies for the development of effective inhibitors. In this respect, phosphorylation has recently come into prominence as this reversible post-translational modification attenuates sensitivity of RAS towards RAF. As such, in this study, we set out to unveil the impact of phosphorylation on dynamics of HRASWT and aim to invoke similar behavior in HRASG12D mutant by means of small therapeutic molecules. To this end, we performed molecular dynamics (MD) simulations using phosphorylated HRAS and showed that phosphorylation of Y32 distorted Switch I, hence the RAS/RAF interface. Consequently, we targeted Switch I in HRASG12D by means of approved therapeutic molecules and showed that the ligands enabled detachment of Switch I from the nucleotide-binding pocket. Moreover, we demonstrated that displacement of Switch I from the nucleotide-binding pocket was energetically more favorable in the presence of the ligand. Importantly, we verified computational findings in vitro where HRASG12D/RAF interaction was prevented by the ligand in HEK293T cells that expressed HRASG12D mutant protein. Therefore, these findings suggest that targeting Switch I, hence making Y32 accessible might open up new avenues in future drug discovery strategies that target mutant RAS proteins.
dc.identifier.citationİlter, M., Kaşmer, R., Jalalypour, F., Atılgan, C., Topçu, O., Karakaş, N. ... Şensoy, Ö. (2022). Inhibition of mutant RAS-RAF interaction by mimicking structural and dynamic properties of phosphorylated RAS. eLife, 11. https://dx.doi.org/10.7554/eLife.79747
dc.identifier.doi10.7554/eLife.79747
dc.identifier.issn2050-084X
dc.identifier.pmid36458814
dc.identifier.scopus2-s2.0-85144588808
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://dx.doi.org/10.7554/eLife.79747
dc.identifier.urihttps://hdl.handle.net/20.500.12511/10260
dc.identifier.volume11
dc.identifier.wos000931390400001en_US
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorİlter, Metehan
dc.institutionauthorKaşmer, Ramazan
dc.institutionauthorTopçu, Ozan
dc.institutionauthorKarakaş, Nihal
dc.institutionauthorŞensoy, Özge
dc.language.isoen
dc.publisherNLM (Medline)
dc.relation.ispartofeLifeen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsAttribution 4.0 International*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subjectEukaryotic Expression Plasmid
dc.subjectHek-293t -Hras-G12d
dc.subjectHek-293t -Hras-Wt
dc.subjectMolecular Biophysics
dc.subjectStructural Biology
dc.titleInhibition of mutant RAS-RAF interaction by mimicking structural and dynamic properties of phosphorylated RAS
dc.typeArticle

Dosyalar

Orijinal paket
Listeleniyor 1 - 1 / 1
Küçük Resim
İsim:
Ilter-Metehan-2022.pdf
Boyut:
9.01 MB
Biçim:
Adobe Portable Document Format
Açıklama:
Tam Metin / Full Text
İndir
Lisans paketi
Listeleniyor 1 - 1 / 1
Küçük Resim Yok
İsim:
license.txt
Boyut:
1.44 KB
Biçim:
Item-specific license agreed upon to submission
Açıklama:
İndir

Koleksiyon

Sağlık Bilimleri Enstitüsü Diğer Yayınlar Koleksiyonu
Makale Koleksiyonu
Makale Koleksiyonu
Makale Koleksiyonu
Makale Koleksiyonu
PubMed İndeksli Yayınlar Koleksiyonu
Daha fazla yükle