PDBsum entry 4pci

Transcription/transcription inhibitor

PDB id

4pci

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Contents

			Protein chain

					126 a.a.

			Ligands

					2NJ


					EDO

			Waters ×145

PDB id:

4pci

Links

Name:

Transcription/transcription inhibitor

Title:

Crystal structure of the first bromodomain of brd4 in complex with b16

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:

1.25Å

R-factor:

0.147

R-free:

0.169

Authors:

J.Dong,A.Caflisch

Key ref:

H.Zhao et al. (2014). Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking. Bioorg Med Chem Lett, 24, 2493-2496. PubMed id: 24767840 DOI: 10.1016/j.bmcl.2014.04.017

Date:

15-Apr-14

Release date:

14-May-14

PROCHECK

	Headers

	References

Protein chain

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

Seq: Struc:

Seq: Struc:

Seq: Struc:					1362 a.a. 126 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

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



		Enzyme reactions

Enzyme class:

E.C.?

[IntEnz] [ExPASy] [KEGG] [BRENDA]

DOI no: 10.1016/j.bmcl.2014.04.017	Bioorg Med Chem Lett 24:2493-2496 (2014)
PubMed id: 24767840

Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking.
H.Zhao, L.Gartenmann, J.Dong, D.Spiliotopoulos, A.Caflisch.

ABSTRACT

Bromodomains (BRDs) recognize acetyl-lysine modified histone tails mediating epigenetic processes. BRD4, a protein containing two bromodomains, has emerged as an attractive therapeutic target for several types of cancer as well as inflammatory diseases. Using a fragment-based in silico screening approach, we identified two small molecules that bind to the first bromodomain of BRD4 with low-micromolar affinity and favorable ligand efficiency (0.37kcal/mol per non-hydrogen atom), selectively over other families of bromodomains. Notably, the hit rate of the fragment-based in silico approach is about 10% as only 24 putative inhibitors, from an initial library of about 9 million molecules, were tested in vitro.