5ENE

Crystal structure of the second bromodomain of Pleckstrin homology domain interacting protein (PHIP) in complex with 5-Amino-2-benzyl-1,3-oxazole-4-carbonitrile (SGC - Diamond I04-1 fragment screening)

Summary for 5ENE

• Entry DOI: 10.2210/pdb5ene/pdb
• Descriptor: PH-interacting protein, 5-azanyl-2-(phenylmethyl)-1,3-oxazole-4-carbonitrile (3 entities in total)
• Functional Keywords: bromodomain, phip, crystallographic fragment screen, transcription, structural genomics, structural genomics consortium, sgc, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15793.87

Authors

Krojer, T.,Talon, R.,Collins, P.,Bradley, A.,Cox, O.,Amin, J.,Szykowska, A.,Burgess-Brown, N.,Spencer, J.,Brennan, P.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,von Delft, F.,Structural Genomics Consortium (SGC) (deposition date: 2015-11-09, release date: 2016-04-27, Last modification date: 2024-01-10)

Primary citation

Cox, O.B.,Krojer, T.,Collins, P.,Monteiro, O.,Talon, R.,Bradley, A.,Fedorov, O.,Amin, J.,Marsden, B.D.,Spencer, J.,von Delft, F.,Brennan, P.E.
A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain.
Chem Sci, 7:2322-2330, 2016

PubMed Abstract: 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 IC 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.

PubMed: 29910922
DOI: 10.1039/c5sc03115j

Experimental method

X-RAY DIFFRACTION (1.49 Å)