Naslov
Binding of peptide mimicking the ETGE loop of dipeptidyl peptidase III to the Kelch domain of Keap1

Autori
Kekez, Ivana ; Matić, Sara ; Tomić, Sanja ; Matković-Čalogović, Dubravka

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
The twenty-eighth Croatian-Slovenian Crystallographic Meeting : Book of Abstracts / - Zagreb, 2022, 8-8

Skup
28th Croatian-Slovenian Crystallographic Meeting 2022 - CCDC

Mjesto i datum
Poreč, Hrvatska, 07.09.2022. - 11.09.2022

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Kelch domain ; ETGE loop ; crystal structure

Sažetak
Signaling pathway of the NRF2 ̶ KEAP1 factor 2 (nuclear factor erythroid 2-related–Kelch like ECH- associated protein 1) is important for cell protection. However, it is impaired in many cancer cells where NRF2 target gene expression leads to resistance to chemotherapeutic drugs. Dipeptidyl peptidase III (DPP III) competitively binds to KEAP1 in the conditions of oxidative stress and induces release of NRF2 and its translocation into nucleus. The binding is established mainly through the ETGE motif located on the flexible loop of DPP III and the Kelch domain of KEAP1. To better understand interactions between DPP III and the Kelch domain of the KEAP1 protein we solved its crystal structure at a resolution of 2.70 Å (Figure 1A). The asymmetric unit contains one protein molecule, one 11-mer peptide molecule mimicking the ETGE loop of the DPP III peptide, nine water molecules, and one sodium ion. The final model was refined to Rwork = 18.1% and Rfree = 25.8%. Clear electron density (Figure 1B) was observed in the difference map near the region involved in the interactions with the ETGE motif, allowing proper fitting of the peptide and determination of the main interactions between the peptide and the Kelch domain of the KEAP1 protein. We found that ETGE itself is firmly attached to the peptide by strong hydrogen bonds in the same way as in the crystal structure of the Kelch–NRF2 complex. The backbone of the 11 AA peptide makes five hydrogen bonds with the Kelch domain, in four of them the peptide residues (P479, E480, T481 and Q484) are hydrogen bond acceptors, and donor in one (Q484).

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA