6XVT

ENAH EVH1 in complex with Ac-[2-Cl-F]-PPPPTEDDL-NH2

6XVT の概要

• エントリーDOI: 10.2210/pdb6xvt/pdb
• 関連するPDBエントリー: 5NC2
• 分子名称: Protein enabled homolog, ACY-SC1-SC2-SC3-SC4-SC5-NME, NITRATE ION, ... (5 entities in total)
• 機能のキーワード: proline-rich motif, acta, ena/vasp inhibitor, actin, protein-protein interaction, cell adhesion
• 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: 26916.98

構造登録者

Barone, M.,Le Cong, K.,Roske, Y. (登録日: 2020-01-22, 公開日: 2020-03-18, 最終更新日: 2024-02-07)

主引用文献

Barone, M.,Muller, M.,Chiha, S.,Ren, J.,Albat, D.,Soicke, A.,Dohmen, S.,Klein, M.,Bruns, J.,van Dinther, M.,Opitz, R.,Lindemann, P.,Beerbaum, M.,Motzny, K.,Roske, Y.,Schmieder, P.,Volkmer, R.,Nazare, M.,Heinemann, U.,Oschkinat, H.,Ten Dijke, P.,Schmalz, H.G.,Kuhne, R.
Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells.
Proc.Natl.Acad.Sci.USA, 117:29684-29690, 2020

PubMed Abstract: Battling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular interactions with their EVH1 domains, are promising targets for pharmaceutical intervention. However, protein-protein interactions involving proline-rich segments are notoriously difficult to address by small molecules. Hence, structure-based design efforts in combination with the chemical synthesis of additional molecular entities are required. Building on a previously developed nonpeptidic micromolar inhibitor, we determined 22 crystal structures of ENAH EVH1 in complex with inhibitors and rationally extended our library of conformationally defined proline-derived modules (ProMs) to succeed in developing a nanomolar inhibitor ([Formula: see text] Da). In contrast to the previous inhibitor, the optimized compounds reduced extravasation of invasive breast cancer cells in a zebrafish model. This study represents an example of successful, structure-guided development of low molecular weight inhibitors specifically and selectively addressing a proline-rich sequence-recognizing domain that is characterized by a shallow epitope lacking defined binding pockets. The evolved high-affinity inhibitor may now serve as a tool in validating the basic therapeutic concept, i.e., the suppression of cancer metastasis by inhibiting a crucial protein-protein interaction involved in actin filament processing and cell migration.

PubMed: 33184177
DOI: 10.1073/pnas.2007213117

実験手法

X-RAY DIFFRACTION (1.4 Å)