PDBsum entry 6e23

Gene regulation/inhibitor

PDB id: 6e23

Contents

Protein chains

299 a.a.

Ligands

HLJ ×2

EPE

Waters ×533

PDB id:

6e23

Name:

Gene regulation/inhibitor

Title:

Displacement of wdr5 from chromatin by a pharmacological win site inhibitor with picomolar affinity

Structure:

Wd repeat-containing protein 5. Chain: a, b. Synonym: bmp2-induced 3-kb gene protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: wdr5, big3. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.66Å R-factor: 0.183 R-free: 0.210

Authors:

J.Phan,S.W.Fesik

Key ref:

E.R.Aho et al. (2019). Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity. Cell Rep, 26, 2916. PubMed id: 30865883 DOI: 10.1016/j.celrep.2019.02.047

Date:

10-Jul-18 Release date: 13-Mar-19

Protein chains

P61964  (WDR5_HUMAN) -  WD repeat-containing protein 5 from Homo sapiens

Seq: 334 a.a.

Struc: 299 a.a.

DOI no: 10.1016/j.celrep.2019.02.047

Cell Rep 26:2916 (2019)

PubMed id: 30865883

Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity.

E.R.Aho, J.Wang, R.D.Gogliotti, G.C.Howard, J.Phan, P.Acharya, J.D.Macdonald, K.Cheng, S.L.Lorey, B.Lu, S.Wenzel, A.M.Foshage, J.Alvarado, F.Wang, J.G.Shaw, B.Zhao, A.M.Weissmiller, L.R.Thomas, C.R.Vakoc, M.D.Hall, S.W.Hiebert, Q.Liu, S.R.Stauffer, S.W.Fesik, W.P.Tansey.

ABSTRACT

The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.