PDBsum entry 5epl

Transcription/transcription inhibitor

PDB id: 5epl

Contents

Protein chains

54 a.a.

58 a.a.

Ligands

5R0-PHE-ALA-LEU-ELY-5R5 ×2

UNX ×8

Waters ×118

PDB id:

5epl

Name:

Transcription/transcription inhibitor

Title:

Crystal structure of chromodomain of cbx4 in complex with inhibitor unc3866

Structure:

E3 sumo-protein ligase cbx4. Chain: a, b. Synonym: chromobox protein homolog 4,polycomb 2 homolog,hpc2. Engineered: yes. Unc3866. Chain: c, d. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cbx4. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: synthetic

Resolution:

1.81Å R-factor: 0.187 R-free: 0.216

Authors:

Y.Liu,W.Tempel,J.R.Walker,J.I.Stuckey,B.M.Dickson,L.I.James,S.V.Frye, C.Bountra,C.H.Arrowsmith,A.M.Edwards,J.Min,Structural Genomics Consortium (Sgc)

Key ref:

J.I.Stuckey et al. (2016). A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1. Nat Chem Biol, 12, 180-187. PubMed id: 26807715 DOI: 10.1038/nchembio.2007

Date:

11-Nov-15 Release date: 23-Dec-15

Protein chain

O00257  (CBX4_HUMAN) -  E3 SUMO-protein ligase CBX4 from Homo sapiens

Seq: 560 a.a.

Struc: 54 a.a.*

Protein chain

O00257  (CBX4_HUMAN) -  E3 SUMO-protein ligase CBX4 from Homo sapiens

Seq: 560 a.a.

Struc: 58 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.2.3.2.- - ?????

DOI no: 10.1038/nchembio.2007

Nat Chem Biol 12:180-187 (2016)

PubMed id: 26807715

A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1.

J.I.Stuckey, B.M.Dickson, N.Cheng, Y.Liu, J.L.Norris, S.H.Cholensky, W.Tempel, S.Qin, K.G.Huber, C.Sagum, K.Black, F.Li, X.P.Huang, B.L.Roth, B.M.Baughman, G.Senisterra, S.G.Pattenden, M.Vedadi, P.J.Brown, M.T.Bedford, J.Min, C.H.Arrowsmith, L.I.James, S.V.Frye.

ABSTRACT

We report the design and characterization of UNC3866, a potent antagonist of the methyllysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently, with a Kd of ∼100 nM for each, and is 6- to 18-fold selective as compared to seven other CBX and CDY chromodomains while being highly selective over >250 other protein targets. X-ray crystallography revealed that UNC3866's interactions with the CBX chromodomains closely mimic those of the methylated H3 tail. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, consistent with the known ability of CBX7 overexpression to confer a growth advantage, whereas UNC4219, a methylated negative control compound, has negligible effects.