PDBsum entry 6v0x

Gene regulation

PDB id: 6v0x

Contents

Protein chain

99 a.a.

Ligands

B49

Waters ×91

PDB id:

6v0x

Name:

Gene regulation

Title:

Crystal structure of the bromodomain of human brd9 bound to sunitinib

Structure:

Bromodomain-containing protein 9. Chain: a. Synonym: rhabdomyosarcoma antigen mu-rms-40.8. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd9, unq3040/pro9856. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: ripl.

Resolution:

1.50Å R-factor: 0.198 R-free: 0.223

Authors:

M.R.Karim,A.Chan,J.Y.Zhu,E.Schonbrunn

Key ref:

R.M.Karim et al. (2020). Structural Basis of Inhibitor Selectivity in the BRD7/9 Subfamily of Bromodomains. J Med Chem, 63, 3227-3237. PubMed id: 32091206 DOI: 10.1021/acs.jmedchem.9b01980

Date:

19-Nov-19 Release date: 11-Mar-20

Protein chain

Q9H8M2  (BRD9_HUMAN) -  Bromodomain-containing protein 9 from Homo sapiens

Seq: 597 a.a.

Struc: 99 a.a.

DOI no: 10.1021/acs.jmedchem.9b01980

J Med Chem 63:3227-3237 (2020)

PubMed id: 32091206

Structural Basis of Inhibitor Selectivity in the BRD7/9 Subfamily of Bromodomains.

R.M.Karim, A.Chan, J.Y.Zhu, E.Schönbrunn.

ABSTRACT

Inhibition of the bromodomain containing protein 9 (BRD9) by small molecules is an attractive strategy to target mutated SWI/SNF chromatin-remodeling complexes in cancer. However, reported BRD9 inhibitors also inhibit the closely related bromodomain-containing protein 7 (BRD7), which has different biological functions. The structural basis for differential potency and selectivity of BRD9 inhibitors is largely unknown because of the lack of structural information on BRD7. Here, we biochemically and structurally characterized diverse inhibitors with varying degrees of potency and selectivity for BRD9 over BRD7. Novel cocrystal structures of BRD7 liganded with new and previously reported inhibitors of five different chemical scaffolds were determined alongside BRD9 and BRD4. We also report the discovery of first-in-class dual bromodomain-kinase inhibitors outside the bromodomain and extraterminal family targeting BRD7 and BRD9. Combined, the data provide a new framework for the development of BRD7/9 inhibitors with improved selectivity or additional polypharmacologic properties.