PDBsum entry 4zc9

Signaling protein/inhibitor

PDB id: 4zc9

Contents

Protein chain

127 a.a.

Ligands

4MW

Waters ×162

PDB id:

4zc9

Name:

Signaling protein/inhibitor

Title:

Crystal structure of the brd4a/db-2-190 complex

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: first bromo domain (unp residues 42-167). Synonym: protein hunk1. Engineered: yes

Source:

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

Resolution:

0.99Å R-factor: 0.141 R-free: 0.146

Authors:

H.-S.Seo,S.Deangelo,J.E.Bradner

Key ref:

G.E.Winter et al. (2015). DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science, 348, 1376-1381. PubMed id: 25999370 DOI: 10.1126/science.aab1433

Date:

15-Apr-15 Release date: 18-Nov-15

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: 10.1126/science.aab1433

Science 348:1376-1381 (2015)

PubMed id: 25999370

DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation.

G.E.Winter, D.L.Buckley, J.Paulk, J.M.Roberts, A.Souza, S.Dhe-Paganon, J.E.Bradner.

ABSTRACT

The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.