PDBsum entry 6pg4

Protein binding/inhibitor

PDB id: 6pg4

Contents

Protein chain

305 a.a.

Ligands

OHG

SO4 ×3

Waters ×393

PDB id:

6pg4

Name:

Protein binding/inhibitor

Title:

Wdr5delta32 bound to (2-methyl-1h-imidazol-4-yl)methanol

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: wdr5, big3. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693

Resolution:

1.60Å R-factor: 0.148 R-free: 0.176

Authors:

M.L.Dennis,T.S.Peat

Key ref:

M.L.Dennis et al. (2019). Fragment screening for a protein-protein interaction inhibitor to WDR5. Struct Dyn, 6, 064701. PubMed id: 31768400 DOI: 10.1063/1.5122849

Date:

24-Jun-19 Release date: 11-Dec-19

Protein chain

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

Seq: 334 a.a.

Struc: 305 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1063/1.5122849

Struct Dyn 6:064701 (2019)

PubMed id: 31768400

Fragment screening for a protein-protein interaction inhibitor to WDR5.

M.L.Dennis, B.J.Morrow, O.Dolezal, A.N.Cuzzupe, A.E.Stupple, J.Newman, J.Bentley, M.Hattarki, S.D.Nuttall, R.C.Foitzik, I.P.Street, P.A.Stupple, B.J.Monahan, T.S.Peat.

ABSTRACT

The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the "WIN" site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry campaign-guided by a suite of high-resolution cocrystal structures with WDR5-progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine; a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 Å) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time (k_d = ∼0.06 s^-1) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics.