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Targeting ligandable pockets on PHD zinc finger domains by a fragment-based approach

DOI: 10.1021/acschembio.7b01093 DOI Help

Authors: Anastasia Amato (University of Dundee) , Xavier Lucas (University of Dundee) , Alessio Bortoluzzi (University of Dundee) , David Wright (University of Dundee) , Alessio Ciulli (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: March 2018
Diamond Proposal Number(s): 14980 , 10071

Open Access Open Access

Abstract: Plant homeodomain (PHD) zinc fingers are histone reader domains that often associate with human diseases. Despite this, they constitute a poorly targeted class of readers, suggesting low ligandability. Here, we describe a successful fragment-based campaign targeting PHD fingers from the proteins BAZ2A and BAZ2B as model systems. We validated a pool of in silico fragments both biophysically and structurally and solved the first crystal structures of PHD zinc fingers in complex with fragments bound to an anchoring pocket at the histone binding site. The best-validated hits were found to displace a histone H3 tail peptide in competition assays. This work identifies new chemical scaffolds that provide suitable starting points for future ligand optimization using structure-guided approaches. The demonstrated ligandability of the PHD reader domains could pave the way for the development of chemical probes to drug this family of epigenetic targets.

Journal Keywords: Binding modes; Peptides and proteins; Ligands; Crystal structure; Screening assays

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Added On: 20/03/2018 10:46


Discipline Tags:

Biochemistry Chemistry Structural biology Biophysics Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)