McMillan, Joel
[VerfasserIn]
;
Einsle, Oliver
[AkademischeR BetreuerIn];
Schüle, Roland
[AkademischeR BetreuerIn]Albert-Ludwigs-Universität Freiburg Fakultät für Chemie und Pharmazie
Identification of fragments binding to CHD1 double chromodomain, an epigenetic reader of KDM1A K114me2 and H3 K4me3
Beschreibung:
Abstract: Prostate cancer is the most common malignancy in men worldwide and the third most common cause of cancer-related deaths [1-3]. Chromosomal rearrangements, such as TMPRSS2-ERG, occur frequently in prostate cancer. Chromosomal rearrangements in prostate cells are dependent on the presence of androgens, such as dihydrotestosterone (DHT). In this study, KDM1A K114 was found to be dimethylated by EHMT2 in prostate cells. CHD1 was shown to bind specifically to KDM1A K114me2. Another potential interaction partner of KDM1A methylated at K114 is the tandem Tudor domain of KDM4A. Androgen-dependent methylation of KDM1A K114 by EHMT2 and recognition by CHD1 controls recruitment of androgen-receptor (AR) to chromatin and therefore AR-dependent gene expression. The EHMT2-KDM1A K114me2-CHD1-AR circuit was also shown to control chromosomal rearrangements, such as TMPRSS2-ERG. A 1.6 Å resolution X-ray co-crystal structure of the CHD1 double chromodomain (DCD) and a KDM1A108 119 K114me2 peptide revealed a unique binding mode that presents an opportunity to develop specific inhibitors of the interaction between CHD1 and KDM1A K114me2. Fragment screening using X ray crystallography identified a total of 53 fragments binding to eight unique sites on CHD1 DCD. A total of 41 fragments were identified to bind at a fragment ‘hotspot’ near the peptide binding interface. Fragments bound at this hotspot could represent good starting points for development of chemical probes specifically blocking the interaction between CHD1 and KDM1A K114me2 but not the other identified methylated interaction partner, H3 K4me3. One fragment was identified that binds to the methyllysine-binding aromatic cage of CHD1 DCD. This is the first reported small molecule bound to the aromatic cage of a DCD. An unexpected fragment binding site was also identified at the methylated peptide binding interface. Fragments bound at this, or the aromatic cage, site could represent starting points for the development of the first chemical probes or inhibitors for a DCD