PDBsum entry 4y7r

DNA binding protein

PDB id: 4y7r

Contents

Protein chain

304 a.a.

Ligands

GLU-GLU-ILE-ASP-VAL-VAL-SER-VAL

TRS

EDO

Waters ×179

PDB id:

4y7r

Name:

DNA binding protein

Title:

Crystal structure of wdr5 in complex with myc mbiiib peptide

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: wdr5, big3. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

1.90Å R-factor: 0.160 R-free: 0.188

Authors:

Q.Sun,J.Phan,E.T.Olejniczak,L.R.Thomas,S.W.Fesik,W.P.Tansey

Key ref:

L.R.Thomas et al. (2015). Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Mol Cell, 58, 440-452. PubMed id: 25818646 DOI: 10.1016/j.molcel.2015.02.028

Date:

16-Feb-15 Release date: 15-Apr-15

Protein chain

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

Seq: 334 a.a.

Struc: 304 a.a.

DOI no: 10.1016/j.molcel.2015.02.028

Mol Cell 58:440-452 (2015)

PubMed id: 25818646

Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC.

L.R.Thomas, Q.Wang, B.C.Grieb, J.Phan, A.M.Foshage, Q.Sun, E.T.Olejniczak, T.Clark, S.Dey, S.Lorey, B.Alicie, G.C.Howard, B.Cawthon, K.C.Ess, C.M.Eischen, Z.Zhao, S.W.Fesik, W.P.Tansey.

ABSTRACT

MYC is an oncoprotein transcription factor that is overexpressed in the majority of malignancies. The oncogenic potential of MYC stems from its ability to bind regulatory sequences in thousands of target genes, which depends on interaction of MYC with its obligate partner, MAX. Here, we show that broad association of MYC with chromatin also depends on interaction with the WD40-repeat protein WDR5. MYC binds WDR5 via an evolutionarily conserved "MYC box IIIb" motif that engages a shallow, hydrophobic cleft on the surface of WDR5. Structure-guided mutations in MYC that disrupt interaction with WDR5 attenuate binding of MYC at ∼80% of its chromosomal locations and disable its ability to promote induced pluripotent stem cell formation and drive tumorigenesis. Our data reveal WDR5 as a key determinant for MYC recruitment to chromatin and uncover a tractable target for the discovery of anticancer therapies against MYC-driven tumors.