4MY6

EnaH-EVH1 in complex with peptidomimetic low-molecular weight inhibitor Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-OH

4MY6 の概要

• エントリーDOI: 10.2210/pdb4my6/pdb
• 関連するBIRD辞書のPRD_ID: PRD_001198
• 分子名称: Protein enabled homolog, (3aR,5aS,8S,10aS)-1-[(3S,6R,8aS)-1'-[(2S)-2-acetamido-3-(2-chlorophenyl)propanoyl]-5-oxidanylidene-spiro[1,2,3,8a-tetrahydroindolizine-6,2'-pyrrolidine]-3-yl]carbonyl-10-oxidanylidene-2,3,3a,5a,8,10a-hexahydrodipyrrolo[3,2-b:3',1'-f]azepine-8-carboxylic acid, BROMIDE ION, ... (4 entities in total)
• 機能のキーワード: molecular recognition, actin dynamics, cell adhesion-inhibitor complex, cell adhesion/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q8N8S7
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 26768.67

構造登録者

Barone, M.,Roske, Y.,Kuehne, R. (登録日: 2013-09-27, 公開日: 2014-10-15, 最終更新日: 2023-09-20)

主引用文献

Opitz, R.,Muller, M.,Reuter, C.,Barone, M.,Soicke, A.,Roske, Y.,Piotukh, K.,Huy, P.,Beerbaum, M.,Wiesner, B.,Beyermann, M.,Schmieder, P.,Freund, C.,Volkmer, R.,Oschkinat, H.,Schmalz, H.G.,Kuhne, R.
A modular toolkit to inhibit proline-rich motif-mediated protein-protein interactions.
Proc.Natl.Acad.Sci.USA, 112:5011-5016, 2015

PubMed Abstract: Small-molecule competitors of protein-protein interactions are urgently needed for functional analysis of large-scale genomics and proteomics data. Particularly abundant, yet so far undruggable, targets include domains specialized in recognizing proline-rich segments, including Src-homology 3 (SH3), WW, GYF, and Drosophila enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Here, we present a modular strategy to obtain an extendable toolkit of chemical fragments (ProMs) designed to replace pairs of conserved prolines in recognition motifs. As proof-of-principle, we developed a small, selective, peptidomimetic inhibitor of Ena/VASP EVH1 domain interactions. Highly invasive MDA MB 231 breast-cancer cells treated with this ligand showed displacement of VASP from focal adhesions, as well as from the front of lamellipodia, and strongly reduced cell invasion. General applicability of our strategy is illustrated by the design of an ErbB4-derived ligand containing two ProM-1 fragments, targeting the yes-associated protein 1 (YAP1)-WW domain with a fivefold higher affinity.

PubMed: 25848013
DOI: 10.1073/pnas.1422054112

実験手法

X-RAY DIFFRACTION (1.7 Å)