7A00

Crystal structure of Shank1 PDZ in complex with L6F mutant of the C-terminal hexapeptide from GKAP

7A00 の概要

• エントリーDOI: 10.2210/pdb7a00/pdb
• 分子名称: SH3 and multiple ankyrin repeat domains protein 1, L6F mutant of C-terminal hexapeptide from Guanylate kinase-associated protein (3 entities in total)
• 機能のキーワード: shank1 pdz, gkap, peptide binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 26238.26

構造登録者

Zsofia, H.,Hetherington, K.,Fruzsina, H.,Edwards, T.A.,Wilson, A.J. (登録日: 2020-08-05, 公開日: 2021-07-07, 最終更新日: 2024-11-06)

主引用文献

Celis, S.,Hobor, F.,James, T.,Bartlett, G.J.,Ibarra, A.A.,Shoemark, D.K.,Hegedus, Z.,Hetherington, K.,Woolfson, D.N.,Sessions, R.B.,Edwards, T.A.,Andrews, D.M.,Nelson, A.,Wilson, A.J.
Query-guided protein-protein interaction inhibitor discovery.
Chem Sci, 12:4753-4762, 2021

PubMed Abstract: Protein-protein interactions (PPIs) are central to biological mechanisms, and can serve as compelling targets for drug discovery. Yet, the discovery of small molecule inhibitors of PPIs remains challenging given the large and typically shallow topography of the interacting protein surfaces. Here, we describe a general approach to the discovery of orthosteric PPI inhibitors that mimic specific secondary protein structures. Initially, hot residues at protein-protein interfaces are identified or from experimental data, and incorporated into secondary structure-based queries. Virtual libraries of small molecules are then shape-matched against the queries, and promising ligands docked to target proteins. The approach is exemplified experimentally using two unrelated PPIs that are mediated by an α-helix (p53/DM2) and a β-strand (GKAP/SHANK1-PDZ). In each case, selective PPI inhibitors are discovered with low μM activity as determined by a combination of fluorescence anisotropy and H-N HSQC experiments. In addition, hit expansion yields a series of PPI inhibitors with defined structure-activity relationships. It is envisaged that the generality of the approach will enable discovery of inhibitors of a wide range of unrelated secondary structure-mediated PPIs.

PubMed: 34163731
DOI: 10.1039/d1sc00023c

実験手法

X-RAY DIFFRACTION (1.78 Å)