PDBsum entry 6sio

Peptide binding protein

PDB id: 6sio

Contents

Protein chains

225 a.a.

12 a.a.

Ligands

LFQ ×2

Metals

_MG ×2

_CL

Waters ×355

PDB id:

6sio

Name:

Peptide binding protein

Title:

Fragment az-017 binding at the p53pt387/14-3-3 sigma interface

Structure:

14-3-3 protein sigma. Chain: a. Synonym: epithelial cell marker protein 1,stratifin. Engineered: yes. Cellular tumor antigen p53. Chain: p. Synonym: antigen ny-co-13,phosphoprotein p53,tumor suppressor p53. 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:

1.60Å R-factor: 0.164 R-free: 0.195

Authors:

S.Leysen,M.Wolter,X.Guillory,S.Genet,B.Somsen,J.Patel,P.Castaldi, C.Ottmann

Key ref:

X.Guillory et al. (2020). Fragment-based Differential Targeting of PPI Stabilizer Interfaces. J Med Chem, 63, 6694-6707. PubMed id: 32501690 DOI: 10.1021/acs.jmedchem.9b01942

Date:

10-Aug-19 Release date: 17-Jun-20

Protein chain

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

Seq: 248 a.a.

Struc: 225 a.a.

Protein chain

P04637  (P53_HUMAN) -  Cellular tumor antigen p53 from Homo sapiens

Seq: 393 a.a.

Struc: 12 a.a.*

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

DOI no: 10.1021/acs.jmedchem.9b01942

J Med Chem 63:6694-6707 (2020)

PubMed id: 32501690

Fragment-based Differential Targeting of PPI Stabilizer Interfaces.

X.Guillory, M.Wolter, S.Leysen, J.F.Neves, A.Kuusk, S.Genet, B.Somsen, J.K.Morrow, E.Rivers, L.van Beek, J.Patel, R.Goodnow, H.Schoenherr, N.Fuller, Q.Cao, R.G.Doveston, L.Brunsveld, M.R.Arkin, P.Castaldi, H.Boyd, I.Landrieu, H.Chen, C.Ottmann.

ABSTRACT

Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3. The fragments discriminately bind to the interface of 14-3-3 with the recognition motif of either the tumor suppressor protein p53 or the oncogenic transcription factor TAZ. This X-ray crystallography driven study shows that the rim of the interface of individual 14-3-3 complexes can be targeted in a differential manner with fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers.