5ND0

ENAH EVH1 in complex with Ac-[2-Cl-F]-PP-[ProM-1]-TEDEL-NH2

5ND0 の概要

• エントリーDOI: 10.2210/pdb5nd0/pdb
• 分子名称: Protein enabled homolog, 5,6-DIHYDRO-BENZO[H]CINNOLIN-3-YLAMINE, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: proline-rich motif, acta, 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: 28210.25

構造登録者

Barone, M.,Roske, Y. (登録日: 2017-03-07, 公開日: 2018-03-21, 最終更新日: 2024-01-31)

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 (1.45 Å)