6wi7

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RING1B-BMI1 fusion in closed conformationRING1B-BMI1 fusion in closed conformation

Structural highlights

6wi7 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.702Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RING2_HUMAN E3 ubiquitin-protein ligase that mediates monoubiquitination of 'Lys-119' of histone H2A, thereby playing a central role in histone code and gene regulation. H2A 'Lys-119' ubiquitination gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. May be involved in the initiation of both imprinted and random X inactivation. Essential component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones, rendering chromatin heritably changed in its expressibility. E3 ubiquitin-protein ligase activity is enhanced by BMI1/PCGF4. Acts as the main E3 ubiquitin ligase on histone H2A of the PRC1 complex, while RING1 may rather act as a modulator of RNF2/RING2 activity.[1] [2] [3] [4] [5] BMI1_HUMAN Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. In the PRC1 complex, it is required to stimulate the E3 ubiquitin-protein ligase activity of RNF2/RING2.[6] [7] [8]

Publication Abstract from PubMed

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.

Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain.,Shukla S, Ying W, Gray F, Yao Y, Simes ML, Zhao Q, Miao H, Cho HJ, Gonzalez-Alonso P, Winkler A, Lund G, Purohit T, Kim E, Zhang X, Ray JM, He S, Nikolaidis C, Ndoj J, Wang J, Jaremko L, Jaremko M, Ryan RJH, Guzman ML, Grembecka J, Cierpicki T Nat Chem Biol. 2021 Jul;17(7):784-793. doi: 10.1038/s41589-021-00815-5. Epub 2021, Jun 21. PMID:34155404[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Lee SJ, Choi JY, Sung YM, Park H, Rhim H, Kang S. E3 ligase activity of RING finger proteins that interact with Hip-2, a human ubiquitin-conjugating enzyme. FEBS Lett. 2001 Aug 10;503(1):61-4. PMID:11513855
  2. ↑ Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones RS, Zhang Y. Role of histone H2A ubiquitination in Polycomb silencing. Nature. 2004 Oct 14;431(7010):873-8. Epub 2004 Sep 22. PMID:15386022 doi:10.1038/nature02985
  3. ↑ Cao R, Tsukada Y, Zhang Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell. 2005 Dec 22;20(6):845-54. PMID:16359901 doi:10.1016/j.molcel.2005.12.002
  4. ↑ Li Z, Cao R, Wang M, Myers MP, Zhang Y, Xu RM. Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex. J Biol Chem. 2006 Jul 21;281(29):20643-9. Epub 2006 May 18. PMID:16714294 doi:10.1074/jbc.M602461200
  5. ↑ Wang R, Taylor AB, Leal BZ, Chadwell LV, Ilangovan U, Robinson AK, Schirf V, Hart PJ, Lafer EM, Demeler B, Hinck AP, McEwen DG, Kim CA. Polycomb group targeting through different binding partners of RING1B C-terminal domain. Structure. 2010 Aug 11;18(8):966-75. PMID:20696397 doi:10.1016/j.str.2010.04.013
  6. ↑ Cao R, Tsukada Y, Zhang Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell. 2005 Dec 22;20(6):845-54. PMID:16359901 doi:10.1016/j.molcel.2005.12.002
  7. ↑ Chagraoui J, Niessen SL, Lessard J, Girard S, Coulombe P, Sauvageau M, Meloche S, Sauvageau G. E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells. Genes Dev. 2006 Aug 1;20(15):2110-20. PMID:16882984 doi:http://dx.doi.org/20/15/2110
  8. ↑ Li Z, Cao R, Wang M, Myers MP, Zhang Y, Xu RM. Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex. J Biol Chem. 2006 Jul 21;281(29):20643-9. Epub 2006 May 18. PMID:16714294 doi:10.1074/jbc.M602461200
  9. ↑ Shukla S, Ying W, Gray F, Yao Y, Simes ML, Zhao Q, Miao H, Cho HJ, Gonzalez-Alonso P, Winkler A, Lund G, Purohit T, Kim E, Zhang X, Ray JM, He S, Nikolaidis C, Ndoj J, Wang J, Jaremko L, Jaremko M, Ryan RJH, Guzman ML, Grembecka J, Cierpicki T. Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain. Nat Chem Biol. 2021 Jul;17(7):784-793. doi: 10.1038/s41589-021-00815-5. Epub 2021, Jun 21. PMID:34155404 doi:http://dx.doi.org/10.1038/s41589-021-00815-5

6wi7, resolution 1.70Å

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