5ENC

Crystal structure of the second bromodomain of Pleckstrin homology domain interacting protein (PHIP) in complex with N-(2,6-Dichlorobenzyl)acetamide (SGC - Diamond I04-1 fragment screening)

5ENC の概要

• エントリーDOI: 10.2210/pdb5enc/pdb
• 分子名称: PH-interacting protein, 1,2-ETHANEDIOL, ~{N}-[[2,6-bis(chloranyl)phenyl]methyl]ethanamide, ... (4 entities in total)
• 機能のキーワード: bromodomain, phip, crystallographic fragment screen, structural genomics, structural genomics consortium, sgc, transcription, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15936.88

構造登録者

Krojer, T.,Talon, R.,Collins, P.,Bradley, A.,Cox, O.,Szykowska, A.,Burgess-Brown, N.,Brennan, P.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,von Delft, F.,Structural Genomics Consortium (SGC) (登録日: 2015-11-09, 公開日: 2016-04-27, 最終更新日: 2024-01-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.59 Å)