PDBsum entry 5enb

Signaling protein

PDB id: 5enb

Contents

Protein chain

123 a.a.

Ligands

5Q5

EDO ×2

Waters ×105

PDB id:

5enb

Name:

Signaling protein

Title:

Crystal structure of the second bromodomain of pleckstrin homology domain interacting protein (phip) in complex with o-tolylthiourea (sgc - diamond i04-1 fragment screening)

Structure:

Ph-interacting protein. Chain: a. Fragment: bromodomain. Synonym: phip,irs-1 ph domain-binding protein,wd repeat-containing protein 11. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: phip, wdr11. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.73Å R-factor: 0.213 R-free: 0.236

Authors:

T.Krojer,R.Talon,P.Collins,A.Bradley,O.Cox,A.Szykowska,N.Burgess- Brown,P.Brennan,C.Bountra,C.H.Arrowsmith,A.Edwards,F.Von Delft, Structural Genomics Consortium (Sgc)

Key ref:

O.B.Cox et al. (2016). A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain. Chem Sci, 7, 2322-2330. PubMed id: 29910922

Date:

09-Nov-15 Release date: 27-Apr-16

Protein chain

Q8WWQ0  (PHIP_HUMAN) -  PH-interacting protein from Homo sapiens

Seq: 1821 a.a.

Struc: 123 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Chem Sci 7:2322-2330 (2016)

PubMed id: 29910922

A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain.

O.B.Cox, T.Krojer, P.Collins, O.Monteiro, R.Talon, A.Bradley, O.Fedorov, J.Amin, B.D.Marsden, J.Spencer, F.von Delft, P.E.Brennan.

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 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.