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Pregled bibliografske jedinice broj: 873472

Human DPP III – Keap1 Interactions : A Combined Experimental And Computational study


Gundić, Mario; Tomić, Antonija; Wade, Rebecca C.; Matovina, Mihaela; Karačić, Zrinka; Kazazić, Saša; Tomić, Sanja
Human DPP III – Keap1 Interactions : A Combined Experimental And Computational study // Croatica chemica acta, 89 (2016), 2; 217-228 doi:10.5562/cca2916 (međunarodna recenzija, članak, znanstveni)


Naslov
Human DPP III – Keap1 Interactions : A Combined Experimental And Computational study

Autori
Gundić, Mario ; Tomić, Antonija ; Wade, Rebecca C. ; Matovina, Mihaela ; Karačić, Zrinka ; Kazazić, Saša ; Tomić, Sanja

Izvornik
Croatica chemica acta (0011-1643) 89 (2016), 2; 217-228

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
'protein-protein interaction' ; dipeptidyl peptidase III ; docking ; molecular dynamics ; Keap1 ; microscale thermophoresis (MST)

Sažetak
Kelch-like ECH associated protein 1 (Keap1) is a cellular sensor for oxidative stress and a negative regulator of the transcription factor Nrf2. Keap1 and Nrf2 control expression of nearly 500 genes with diverse cytoprotective functions and the Nrf2-Keap1 signaling pathway is a major regulator of cytoprotective responses to oxidative and electrophilic stress. It was found that the metallopeptidase dipeptidyl peptidase III (DPP III) contributes to Nrf2 activation by binding to Keap1, probably by binding to the Kelch domain, and thereby influences Nrf2 activity in cancer. We here first determined that the KD of the DPP III-Kelch domain complex is in the submicromolar range. In order to elucidate the molecular details of the DPP III – Kelch interaction we then built models of the complex between human DPP III and the Keap1 Kelch domain and performed coarse-grained and atomistic simulations of the complexes. In the most stable complexes, the ETGE motif in the DPP III flexible loop binds near the central pore of the six-blade β-propeller Kelch domain. According to the preliminary HD exchange experiments DPP III binds to the more unstructured end of Kelch domain. According to the results of MD simulations DPP III binding to the Kelch domain does not influence the overall DPP III structure or the long-range domain fluctuations. We can conclude that DPP III forms the stable complexes with the Keap1 Kelch domain by inserting the flexible loop into the entrance to the central pore of the six blade β- propeller Kelch domain at its more unstructured, N-terminus.

Izvorni jezik
Engleski

Znanstvena područja
Kemija



POVEZANOST RADA


Projekt / tema
HRZZ-IP-2013-11-7235 - Povezanost fleksibilnosti, aktivnosti i strukture u porodici dipeptidil-peptidaza III (Sanja Tomić, )

Ustanove
Institut "Ruđer Bošković", Zagreb,
Prirodoslovno-matematički fakultet, Zagreb

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI


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