5XPI
Structure of UHRF1 TTD in complex with NV01
Summary for 5XPI
| Entry DOI | 10.2210/pdb5xpi/pdb |
| Descriptor | E3 ubiquitin-protein ligase UHRF1, N-[3-(diethylamino)propyl]-2-(12-methyl-9-oxidanylidene-5-thia-1,10,11-triazatricyclo[6.4.0.0^2,6]dodeca-2(6),3,7,11-tetraen-10-yl)ethanamide (3 entities in total) |
| Functional Keywords | ttd domain, small molecule, ligase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 18825.04 |
| Authors | |
| Primary citation | Senisterra, G.,Zhu, H.Y.,Luo, X.,Zhang, H.,Xun, G.,Lu, C.,Xiao, W.,Hajian, T.,Loppnau, P.,Chau, I.,Li, F.,Allali-Hassani, A.,Atadja, P.,Oyang, C.,Li, E.,Brown, P.J.,Arrowsmith, C.H.,Zhao, K.,Yu, Z.,Vedadi, M. Discovery of Small-Molecule Antagonists of the H3K9me3 Binding to UHRF1 Tandem Tudor Domain SLAS Discov, 23:930-940, 2018 Cited by PubMed Abstract: Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a multidomain protein that plays a critical role in maintaining DNA methylation patterns through concurrent recognition of hemimethylated DNA and histone marks by various domains, and recruitment of DNA methyltransferase 1 (DNMT1). UHRF1 is overexpressed in various cancers, including breast cancer. The tandem tudor domain (TTD) of UHRF1 specifically and tightly binds to histone H3 di- or trimethylated at lysine 9 (H3K9me2 or H3K9me3, respectively), and this binding is essential for UHRF1 function. We developed an H3K9me3 peptide displacement assay, which was used to screen a library of 44,000 compounds for small molecules that disrupt the UHRF1-H3K9me3 interaction. This screen resulted in the identification of NV01, which bound to UHRF1-TTD with a K value of 5 μM. The structure of UHRF1-TTD in complex with NV01 confirmed binding to the H3K9me3-binding pocket. Limited structure-based optimization of NV01 led to the discovery of NV03 (K of 2.4 μM). These well-characterized small-molecule antagonists of the UHRF1-H3K9me2/3 interaction could be valuable starting chemical matter for developing more potent and cell-active probes toward further characterizing UHRF1 function, with possible applications as anticancer therapeutics. PubMed: 29562800DOI: 10.1177/2472555218766278 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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