ISDA: 7MR8

Deposition Date 2021-05-07

Release Date 2022-05-11

Last Version Date 2026-07-29

Entry Detail

PDB ID:

7MR8

Keywords:

GENE REGULATION

Title:

Crystal structure of the first bromodomain (BD1) of human BRD4 bound to GXH-II-076

Biological Source:

Source Organism(s):

Homo sapiens (Taxon ID: 9606)

Expression System(s):

Escherichia coli bl21(de3)

Method Details:

Experimental Method:

X-RAY DIFFRACTION

Resolution:

1.20 Å

R-Value Free:

0.17

R-Value Work:

0.16

R-Value Observed:

0.16

Space Group:

P 21 21 21

Download Validation Report

Macromolecular Entities

Structures with similar UniProt ID

Structural Superimposition Protein Blast

Polymer Type:polypeptide(L)
Molecule:Bromodomain-containing protei
Gene (Uniprot):BRD4
Chain IDs:A
Chain Length:127
Number of Molecules:1
Biological Source:Homo sapiens

UniProt ID:O60885 Pfam ID:PF00439

Ligand Molecules

EDO

ZNJ

Primary Citation

Structural Basis for BD1-Preferring 2,4-Disubstituted Pyrimidine BRDT Inhibitors.

Liang, T, Guan, X, Chan, A, Kalra, P, Shi, R, Solberg, J, Sigua, L.H, Qi, J, Pomerantz, W.C.K, Schonbrunn, E, Hawkinson, J.E, Georg, G.I.Show

J.Med.Chem. 69 11088 11108 (2026)

PMID: 41984625 DOI: 10.1021/acs.jmedchem.6c00180

Abstact

The first bromodomain of the BET protein BRDT (BRDT-BD1) possesses a unique Arg54 residue at the terminus of the ZA channel, absent in other BET family members. We explored this structural uniqueness with 23 analogs of the BET/kinase inhibitor SG3-179, each bearing an amino acid side chain to enable potential interactions between the positively charged arginine group and the negatively charged carboxylate groups. In an AlphaScreen assay, serine analog 13 showed 35-fold selectivity for BRDT-T over BRD4-T. The BRDT-BD1 cocrystal structure with glutamic acid analog 14 showed no interaction with Arg54, suggesting that the observed preference may be related to differences in the structured water molecules. Compound 13 displayed exceptional in vitro metabolic stability but had limited cellular permeability in MDCK-MDR1 cells. Compounds 13 and 14 are among the best BRDT-BD1-preferring inhibitors reported to date and demonstrate a significant step toward identifying highly selective BRDT inhibitors for male contraception.

Legend

Protein

Chemical

Disease

Primary Citation of related structures

Abstact

Feedback Form