PDBsum entry 6t2f

Peptide binding protein

PDB id: 6t2f

Contents

Protein chains

85 a.a.

14 a.a.

Ligands

M9H

Waters ×51

PDB id:

6t2f

Name:

Peptide binding protein

Title:

Multicomponent peptide stapling as a diversity-driven tool for the development of inhibitors of protein-protein interactions

Structure:

E3 ubiquitin-protein ligase mdm2. Chain: a. Synonym: double minute 2 protein,hdm2,oncoprotein mdm2,ring-type e3 ubiquitin transferase mdm2,p53-binding protein mdm2. Engineered: yes. Mutation: yes. Mdm2 in complex with gar300-am. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mdm2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

2.09Å R-factor: 0.198 R-free: 0.272

Authors:

R.M.Groves,M.A.Ali,J.Atmaj,N.Van Oosterwijk,A.Domling,G.D.Rivera, G.M.Ricardo

Key ref:

M.G.Ricardo et al. (2020). Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions. Angew Chem Int Ed Engl, 59, 5235-5241. PubMed id: 31944488 DOI: 10.1002/anie.201916257

Date:

08-Oct-19 Release date: 29-Jan-20

Protein chain

Q00987  (MDM2_HUMAN) -  E3 ubiquitin-protein ligase Mdm2 from Homo sapiens

Seq: 491 a.a.

Struc: 85 a.a.*

Protein chain

No UniProt id for this chain

Struc: 14 a.a.

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

Enzyme reactions

• Enzyme class: Chain A: E.C.2.3.2.27 - RING-type E3 ubiquitin transferase.
• Reaction: S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N₆- ubiquitinyl-[acceptor protein]-L-lysine

DOI no: 10.1002/anie.201916257

Angew Chem Int Ed Engl 59:5235-5241 (2020)

PubMed id: 31944488

Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions.

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.

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.