PDBsum entry 4up5

Transcription

PDB id: 4up5

Contents

Protein chain

85 a.a.

Ligands

94W

Metals

_ZN ×2

Waters ×36

PDB id:

4up5

Name:

Transcription

Title:

Crystal structure of the pygo2 phd finger in complex with the b9l hd1 domain and a chemical fragment

Structure:

Pygopus homolog 2, b-cell cll/lymphoma 9-like protein. Chain: a. Fragment: phd finger, hd1,residues 327-387,240-268. Synonym: pygo2, b9l, b-cell lymphoma 9-like protein, bcl9-like protein, protein bcl9-2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: codonplus ril.

Resolution:

1.65Å R-factor: 0.183 R-free: 0.211

Authors:

T.C.R.Miller,M.Fiedler,T.J.Rutherford,K.Birchall,J.Chugh,M.Bienz

Key ref:

T.C.Miller et al. (2014). Competitive binding of a benzimidazole to the histone-binding pocket of the Pygo PHD finger. Acs Chem Biol, 9, 2864-2874. PubMed id: 25323450 DOI: 10.1021/cb500585s

Date:

12-Jun-14 Release date: 05-Nov-14

Protein chain

Q86UU0  (BCL9L_HUMAN) -  B-cell CLL/lymphoma 9-like protein from Homo sapiens

Seq: 1499 a.a.

Struc: 85 a.a.*

Protein chain

Q9BRQ0  (PYGO2_HUMAN) -  Pygopus homolog 2 from Homo sapiens

Seq: 406 a.a.

Struc: 85 a.a.*

* PDB and UniProt seqs differ at 79 residue positions (black crosses)

DOI no: 10.1021/cb500585s

Acs Chem Biol 9:2864-2874 (2014)

PubMed id: 25323450

Competitive binding of a benzimidazole to the histone-binding pocket of the Pygo PHD finger.

T.C.Miller, T.J.Rutherford, K.Birchall, J.Chugh, M.Fiedler, M.Bienz.

ABSTRACT

The Pygo-BCL9 complex is a chromatin reader, facilitating β-catenin-mediated oncogenesis, and is thus emerging as a potential therapeutic target for cancer. Its function relies on two ligand-binding surfaces of Pygo's PHD finger that anchor the histone H3 tail methylated at lysine 4 (H3K4me) with assistance from the BCL9 HD1 domain. Here, we report the first use of fragment-based screening by NMR to identify small molecules that block protein-protein interactions by a PHD finger. This led to the discovery of a set of benzothiazoles that bind to a cleft emanating from the PHD-HD1 interface, as defined by X-ray crystallography. Furthermore, we discovered a benzimidazole that docks into the H3K4me specificity pocket and displaces the native H3K4me peptide from the PHD finger. Our study demonstrates the ligandability of the Pygo-BCL9 complex and uncovers a privileged scaffold as a template for future development of lead inhibitors of oncogenesis.