PDBsum entry 6t2d

Peptide binding protein

PDB id: 6t2d

Contents

Protein chains

85 a.a.

14 a.a.

Ligands

EPE

DMS

M9E

Waters ×124

References listed in PDB file

Key reference

• Title: Multicomponent peptide stapling as a diversity-Driven tool for the development of inhibitors of protein-Protein interactions.
• Authors: M.G.Ricardo, A.M.Ali, J.Plewka, E.Surmiak, B.Labuzek, C.G.Neochoritis, J.Atmaj, L.Skalniak, R.Zhang, T.A.Holak, M.Groves, D.G.Rivera, A.Dömling.
• Ref.: Angew Chem Int Ed Engl, 2020, 59, 5235-5241. [DOI no: 10.1002/anie.201916257]
• PubMed id: 31944488

Abstract

Stapled peptides are chemical entities in-between biologics and small molecules, which have proven to be the solution to high affinity protein-protein interaction antagonism, while keeping control over pharmacological performance such as stability and membrane penetration. We demonstrate that the multicomponent reaction-based stapling is an effective strategy for the development of α-helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53-MDM2/X interactions was assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both exo- and endo-cyclic hydrophobic moieties at the side chain cross-linkers. The interaction of the Ugi-staple fragments with the target protein was demonstrated by crystallography.