5TTW

Crystal Structure of EED in Complex with UNC4859

Summary for 5TTW

• Entry DOI: 10.2210/pdb5ttw/pdb
• Related: 3K26
• Descriptor: Polycomb protein EED, UNC4859, SULFATE ION, ... (5 entities in total)
• Functional Keywords: wd40, eed peptide inhibitor, transcription regulator-inhibitor complex, transcription regulator/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: O75530
• Total number of polymer chains: 4
• Total formula weight: 86170.25

Authors

The, J.,Barnash, K.D.,Brown, P.J.,Edwards, A.M.,Bountra, C.,Frye, S.V.,James, L.I.,Arrowsmith, C.H. (deposition date: 2016-11-04, release date: 2017-01-11, Last modification date: 2023-10-04)

Primary citation

Barnash, K.D.,The, J.,Norris-Drouin, J.L.,Cholensky, S.H.,Worley, B.M.,Li, F.,Stuckey, J.I.,Brown, P.J.,Vedadi, M.,Arrowsmith, C.H.,Frye, S.V.,James, L.I.
Discovery of Peptidomimetic Ligands of EED as Allosteric Inhibitors of PRC2.
ACS Comb Sci, 19:161-172, 2017

PubMed Abstract: The function of EED within polycomb repressive complex 2 (PRC2) is mediated by a complex network of protein-protein interactions. Allosteric activation of PRC2 by binding of methylated proteins to the embryonic ectoderm development (EED) aromatic cage is essential for full catalytic activity, but details of this regulation are not fully understood. EED's recognition of the product of PRC2 activity, histone H3 lysine 27 trimethylation (H3K27me3), stimulates PRC2 methyltransferase activity at adjacent nucleosomes leading to H3K27me3 propagation and, ultimately, gene repression. By coupling combinatorial chemistry and structure-based design, we optimized a low-affinity methylated jumonji, AT-rich interactive domain 2 (Jarid2) peptide to a smaller, more potent peptidomimetic ligand (K = 1.14 ± 0.14 μM) of the aromatic cage of EED. Our strategy illustrates the effectiveness of applying combinatorial chemistry to achieve both ligand potency and property optimization. Furthermore, the resulting ligands, UNC5114 and UNC5115, demonstrate that targeted disruption of EED's reader function can lead to allosteric inhibition of PRC2 catalytic activity.

PubMed: 28165227
DOI: 10.1021/acscombsci.6b00174

Experimental method

X-RAY DIFFRACTION (1.74 Å)