6WI7
RING1B-BMI1 fusion in closed conformation
Summary for 6WI7
| Entry DOI | 10.2210/pdb6wi7/pdb |
| Descriptor | E3 ubiquitin-protein ligase RING2, Polycomb complex protein BMI-1 chimera, ZINC ION, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total) |
| Functional Keywords | e3 ubiquitin ligase, ring1b, bmi1, ligase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 24914.75 |
| Authors | Cho, H.J.,Cierpicki, T. (deposition date: 2020-04-08, release date: 2021-04-14, Last modification date: 2024-05-22) |
| Primary citation | Shukla, S.,Ying, W.,Gray, F.,Yao, Y.,Simes, M.L.,Zhao, Q.,Miao, H.,Cho, H.J.,Gonzalez-Alonso, P.,Winkler, A.,Lund, G.,Purohit, T.,Kim, E.,Zhang, X.,Ray, J.M.,He, S.,Nikolaidis, C.,Ndoj, J.,Wang, J.,Jaremko, L.,Jaremko, M.,Ryan, R.J.H.,Guzman, M.L.,Grembecka, J.,Cierpicki, T. Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain. Nat.Chem.Biol., 17:784-793, 2021 Cited by PubMed Abstract: Polycomb repressive complex 1 (PRC1) is an essential chromatin-modifying complex that monoubiquitinates histone H2A and is involved in maintaining the repressed chromatin state. Emerging evidence suggests PRC1 activity in various cancers, rationalizing the need for small-molecule inhibitors with well-defined mechanisms of action. Here, we describe the development of compounds that directly bind to RING1B-BMI1, the heterodimeric complex constituting the E3 ligase activity of PRC1. These compounds block the association of RING1B-BMI1 with chromatin and inhibit H2A ubiquitination. Structural studies demonstrate that these inhibitors bind to RING1B by inducing the formation of a hydrophobic pocket in the RING domain. Our PRC1 inhibitor, RB-3, decreases the global level of H2A ubiquitination and induces differentiation in leukemia cell lines and primary acute myeloid leukemia (AML) samples. In summary, we demonstrate that targeting the PRC1 RING domain with small molecules is feasible, and RB-3 represents a valuable chemical tool to study PRC1 biology. PubMed: 34155404DOI: 10.1038/s41589-021-00815-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.702 Å) |
Structure validation
Download full validation report
