Targeting Ligandable Pockets on Plant Homeodomain
(PHD) Zinc Finger Domains by a Fragment-Based Approach
Version 2 2018-03-23, 17:20
Version 1 2018-03-20, 15:34
Posted on 2018-03-23 - 17:20
Plant homeodomain
(PHD) zinc fingers are histone reader domains
that are often associated 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 readers.
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Amato, Anastasia; Lucas, Xavier; Bortoluzzi, Alessio; Wright, David; Ciulli, Alessio (2018). Targeting Ligandable Pockets on Plant Homeodomain
(PHD) Zinc Finger Domains by a Fragment-Based Approach. ACS Publications. Collection. https://doi.org/10.1021/acschembio.7b01093
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AUTHORS (5)
AA
Anastasia Amato
XL
Xavier Lucas
AB
Alessio Bortoluzzi
DW
David Wright
AC
Alessio Ciulli
KEYWORDS
PHD reader domainsmodel systemshistone H 3 tail peptidecompetition assayschemical scaffoldscrystal structuresfragment-based campaignsilico fragmentsFragment-Based Approach Plant homeodomainBAZ 2BPHD fingersPlant Homeodomainhistone binding siteligandabilitystructure-guided approachesbest-validated hitsTargeting Ligandable Pocketszinc fingersfuture ligand optimizationZinc Finger Domainshistone reader domainsPHD zinc fingerschemical probesproteins BAZ 2A