PDBsum entry 6yow

Peptide binding protein

PDB id: 6yow

Contents

Protein chain

232 a.a.

Ligands

ALA-GLY-SEP-ILE-PRO-GLY-ARG-ARG-SER

L3Y

Waters ×359

PDB id:

6yow

Name:

Peptide binding protein

Title:

14-3-3 sigma with rela/p65 binding site ps45 and covalently bound tcf521

Structure:

14-3-3 protein sigma. Chain: a. Synonym: epithelial cell marker protein 1,stratifin. Engineered: yes. P65ps45. Chain: p. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: sfn, hme1. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.23Å R-factor: 0.176 R-free: 0.197

Authors:

M.Wolter,C.Ottmann

Key ref:

M.Wolter et al. (2020). Fragment-Based Stabilizers of Protein-Protein Interactions through Imine-Based Tethering. Angew Chem Int Ed Engl, 59, 21520-21524. PubMed id: 32816380 DOI: 10.1002/anie.202008585

Date:

15-Apr-20 Release date: 23-Sep-20

Protein chain

P31947  (1433S_HUMAN) -  14-3-3 protein sigma from Homo sapiens

Seq: 248 a.a.

Struc: 232 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1002/anie.202008585

Angew Chem Int Ed Engl 59:21520-21524 (2020)

PubMed id: 32816380

Fragment-Based Stabilizers of Protein-Protein Interactions through Imine-Based Tethering.

M.Wolter, D.Valenti, P.J.Cossar, L.M.Levy, S.Hristeva, T.Genski, T.Hoffmann, L.Brunsveld, D.Tzalis, C.Ottmann.

ABSTRACT

Small-molecule stabilization of protein-protein interactions (PPIs) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a "bottom-up" approach is largely unanswered. We report a novel concept for identifying initial chemical matter for PPI stabilization based on imine-forming fragments. The imine bond offers a covalent anchor for site-directed fragment targeting, whereas its transient nature enables efficient analysis of structure-activity relationships. This bond enables fragment identification and optimisation using protein crystallography. We report novel fragments that bind specifically to a lysine at the PPI interface of the p65-subunit-derived peptide of NF-κB with the adapter protein 14-3-3. Those fragments that subsequently establish contacts with the p65-derived peptide, rather than with 14-3-3, efficiently stabilize the 14-3-3/p65 complex and offer novel starting points for molecular glues.