TY  - EJOUR
AU  - Kotlarek, Daria
AU  - Dudek, Katarzyna
AU  - Woźniak, Bartosz
AU  - Pastok, Martyna
AU  - Shishov, Dmitrii
AU  - Cottens, Sylvain
AU  - Biśta, Michał
AU  - Krzywiecka, Emilia
AU  - Górecka-Minakowska, Karolina
AU  - Jurczak, Kinga
AU  - Drmota, Tomas
AU  - Adamczyk, Justyna
AU  - Faliński, Szymon
AU  - Gajewska, Daria
AU  - Klejnot, Marta
AU  - Król, Aleksandra
AU  - Cuprych-Belter, Monika
AU  - Mames, Iwona
AU  - Mathieu, Arnaud
AU  - Podkówka, Aleksandra
AU  - Przytulski, Kamil
AU  - Skowron, Alicja N.
AU  - Sypień, Magdalena
AU  - Takagi, Toshimitsu
AU  - Wanat, Weronika
AU  - Wierzbicki, Igor H.
AU  - Wisniewski, Janusz
AU  - Szlachcic, Anna
AU  - Pokładek, Ziemowit
AU  - Walczak, Michał J.
TI  - Exploration of chemical probes and conformational flexibility of GID4 - the substrate receptor of human CTLH E3 ligase complex
CY  - Biorxiv
M1  - PUBDB-2025-02299
PY  - 2025
N1  - Door proposal: P-20010353;	INDU-22-L03 - Captor Therapeutics Inc., long-term agreementThe project nr POIR.01.01.01-00-0931/19 “Development of an integrated technology platform in the field of targeted protein degradation and its implementation to the pharmaceutical market” was co-financed by the European Regional Development Fund.
AB  - The application of targeted protein degradation (TPD) is currently constrained by the limited availability of low-molecular-weight molecules that can recruit E3 ligases other than CRBN (Cereblon) or VHL (Von Hippel-Lindau ligase). In this study, we present the structure-based drug design (SBDD) of high-affinity ligands that engage E3 ligase GID4 (Glucose-induced degradation protein 4) in biophysical and cellular experiments. Through structural studies and molecular modeling, we identified three groups (clusters) of compounds that induce distinct conformations of GID4. We identified potential exit vectors and used the most promising ligand as a building block to prepare bifunctional degraders in the form of proteolysis-targeting chimeras (PROTACs). Although ternary complex formation was successful in vitro, degradation of BRD4 was not observed, highlighting the need for further optimization of the degraders. We also theoretically investigated the likelihood of the identified GID4 conformations participating in protein-protein interactions mediated by molecular glue mechanisms. We believe the expanded ligand diversity discovered in this study may pave the way for tuning the selectivity and efficacy of protein-protein interactions involving GID4 and its neosubstrates.
LB  - PUB:(DE-HGF)25
DO  - DOI:10.1101/2025.07.01.662521
UR  - https://bib-pubdb1.desy.de/record/632973
ER  -