PDBsum entry 4mep

Transcription/transcription inhibitor

PDB id: 4mep

Contents

Protein chain

127 a.a.

Ligands

24Y

Waters ×114

PDB id:

4mep

Name:

Transcription/transcription inhibitor

Title:

Crystal structure of the first bromodomain of human brd4 in complex with a 3-chloro-pyridone ligand

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: unp residues 44-168. Synonym: protein hunk1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, hunk1. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.85Å R-factor: 0.187 R-free: 0.235

Authors:

P.Filippakopoulos,S.Picaud,I.Felletar,S.Martin,O.Fedorov,L.R.Vidler, N.Brown,F.Von Delft,C.H.Arrowsmith,A.M.Edwards,J.Weigelt,C.Bountra, S.Hoelder,S.Knapp,Structural Genomics Consortium (Sgc)

Key ref:

L.R.Vidler et al. (2013). Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening. J Med Chem, 56, 8073-8088. PubMed id: 24090311 DOI: 10.1021/jm4011302

Date:

27-Aug-13 Release date: 25-Sep-13

Protein chain

O60885  (BRD4_HUMAN) -  Bromodomain-containing protein 4 from Homo sapiens

Seq: 1362 a.a.

Struc: 127 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/jm4011302

J Med Chem 56:8073-8088 (2013)

PubMed id: 24090311

Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening.

L.R.Vidler, P.Filippakopoulos, O.Fedorov, S.Picaud, S.Martin, M.Tomsett, H.Woodward, N.Brown, S.Knapp, S.Hoelder.

ABSTRACT

Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.