PDBsum entry 6tjm

Signaling protein

PDB id: 6tjm

Contents

Protein chain

229 a.a.

Ligands

PHE-PRO-ALA-TPO-VAL

NE5

Metals

_MG

Waters ×127

PDB id:

6tjm

Name:

Signaling protein

Title:

Crystal structure of an estrogen receptor alpha 8-mer phosphopeptide in complex with 14-3-3sigma stabilized by pyrrolidone1

Structure:

14-3-3 protein sigma. Chain: a. Synonym: epithelial cell marker protein 1,stratifin. Engineered: yes. C-terminal phosphopeptide of human estrogen receptor alpha. Chain: b. 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:

1.85Å R-factor: 0.198 R-free: 0.218

Authors:

S.A.Andrei,F.Bosica,C.Ottmann,G.O'Mahony

Key ref:

F.Bosica et al. (2020). Design of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization. Chemistry, 26, 7131-7139. PubMed id: 32255539 DOI: 10.1002/chem.202001608

Date:

26-Nov-19 Release date: 29-Apr-20

Protein chain

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

Seq: 248 a.a.

Struc: 229 a.a.

DOI no: 10.1002/chem.202001608

Chemistry 26:7131-7139 (2020)

PubMed id: 32255539

Design of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization.

F.Bosica, S.A.Andrei, J.F.Neves, P.Brandt, A.Gunnarsson, I.Landrieu, C.Ottmann, G.O'Mahony.

ABSTRACT

Protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such studies have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg²⁺ leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective, and drug-like 14-3-3 PPI stabilizers.