5ENJ: Crystal structure of the second bromodomain of Pleckstrin homology domain interacting protein (PHIP) in complex with compound-14 N11530 (SGC - Diamond I04-1 fragment screening)

Research into the chemical biology of bromodomains has been driven by the development of acetyl-lysine mimetics. The ligands are typically anchored by binding to a highly conserved asparagine residue. Atypical bromodomains, for which the asparagine is mutated, have thus far proven elusive targets, including PHIP(2) whose parent protein, PHIP, has been linked to disease progression in diabetes and cancers. The PHIP(2) binding site contains a threonine in place of asparagine, and solution screening have yielded no convincing hits. We have overcome this hurdle by combining the sensitivity of X-ray crystallography, used as the primary fragment screen, with a strategy for rapid follow-up synthesis using a chemically-poised fragment library, which allows hits to be readily modified by parallel chemistry both peripherally and in the core. Our approach yielded the first reported hit compounds of PHIP(2) with measurable IC50 values by an AlphaScreen competition assay. The follow-up libraries of four poised fragment hits improved potency into the sub-mM range while showing good ligand efficiency and detailed structural data.
PDB ID: 5ENJDownload
MMDB ID: 138546
PDB Deposition Date: 2015/11/9
Updated in MMDB: 2018/07
Experimental Method:
x-ray diffraction
Resolution: 1.63  Å
Source Organism:
Similar Structures:
Biological Unit for 5ENJ: monomeric; determined by author and by software (PISA)
Molecular Components in 5ENJ
Label Count Molecule
Protein (1 molecule)
Ph-interacting Protein(Gene symbol: PHIP)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB