5AFG

Structure of the Stapled Peptide Bound to Mdm2

5AFG の概要

• エントリーDOI: 10.2210/pdb5afg/pdb
• 分子名称: E3 UBIQUITIN-PROTEIN LIGASE MDM2, STAPLED PEPTIDE, 1,8-DIETHYL-1,8-DIHYDRODIBENZO[3,4:7,8][1,2,3]TRIAZOLO[4',5':5,6]CYCLOOCTA[1,2-D][1,2,3]TRIAZOLE, ... (4 entities in total)
• 機能のキーワード: ligase, mdm2
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 12865.93

構造登録者

Lau, Y.H.,Wu, Y.,Rossmann, M.,de Andrade, P.,Tan, Y.S.,McKenzie, G.J.,Venkitaraman, A.R.,Hyvonen, M.,Spring, D.R. (登録日: 2015-01-22, 公開日: 2016-01-27, 最終更新日: 2024-01-10)

主引用文献

Lau, Y.H.,Wu, Y.,Rossmann, M.,Tan, B.X.,De Andrade, P.,Tan, Y.S.,Verma, C.,Mckenzie, G.J.,Venkitaraman, A.R.,Hyvonen, M.,Spring, D.R.
Double Strain-Promoted Macrocyclization for the Rapid Selection of Cell-Active Stapled Peptides.
Angew.Chem.Int.Ed.Engl., 54:15410-, 2015

PubMed Abstract: Peptide stapling is a method for designing macrocyclic alpha-helical inhibitors of protein-protein interactions. However, obtaining a cell-active inhibitor can require significant optimization. We report a novel stapling technique based on a double strain-promoted azide-alkyne reaction, and exploit its biocompatibility to accelerate the discovery of cell-active stapled peptides. As a proof of concept, MDM2-binding peptides were stapled in parallel, directly in cell culture medium in 96-well plates, and simultaneously evaluated in a p53 reporter assay. This in situ stapling/screening process gave an optimal candidate that showed improved proteolytic stability and nanomolar binding to MDM2 in subsequent biophysical assays. α-Helicity was confirmed by a crystal structure of the MDM2-peptide complex. This work introduces in situ stapling as a versatile biocompatible technique with many other potential high-throughput biological applications.

PubMed: 26768531
DOI: 10.1002/ANIE.201508416

実験手法

X-RAY DIFFRACTION (1.9 Å)