PDBsum entry 5dfc

Transcription

PDB id

5dfc

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Contents

			Protein chain

					109 a.a.

			Ligands

					GOL


					2PE


					EAM

			Metals

					_NI

			Waters ×84

PDB id:

5dfc

Links

Name:

Transcription

Title:

Crystal structure of brd2(bd2) w370f mutant with ligand i-bet 762 bound

Structure:

Bromodomain-containing protein 2. Chain: a. Fragment: residues 344-455. Synonym: o27.1.1,really interesting new gene 3 protein. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd2, kiaa9001, ring3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.50Å

R-factor:

0.157

R-free:

0.171

Authors:

C.Tallant,M.Baud,E.Lin-Shiao,D.Y.Chirgadze,A.Ciulli

Key ref:

M.G.Baud et al. (2016). New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition. J Med Chem, 59, 1492-1500. PubMed id: 26367539 DOI: 10.1021/acs.jmedchem.5b01135

Date:

26-Aug-15

Release date:

11-Nov-15

PROCHECK

	Headers

	References

Protein chain

P25440 (BRD2_HUMAN) - Bromodomain-containing protein 2 from Homo sapiens

Seq: Struc:

Seq: Struc:					801 a.a. 109 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

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

DOI no: 10.1021/acs.jmedchem.5b01135	J Med Chem 59:1492-1500 (2016)
PubMed id: 26367539

New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition.
M.G.Baud, E.Lin-Shiao, M.Zengerle, C.Tallant, A.Ciulli.

ABSTRACT

We describe new synthetic routes developed toward a range of substituted analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1 based on the triazolo-benzodiazepine scaffold. These new routes allow for the derivatization of the methoxyphenyl and chlorophenyl rings, in addition to the diazepine ternary center and the side chain methylene moiety. Substitution at the level of the side chain methylene afforded compounds targeting specifically and potently engineered BET bromodomains designed as part of a bump and hole approach. We further demonstrate that marked selectivity for the second over the first bromodomain can be achieved with an indole derivative that exploits differential interaction with an aspartate/histidine conservative substitution on the BC loop of BET bromodomains.