5NBF

ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-3]-OH

5NBF の概要

• エントリーDOI: 10.2210/pdb5nbf/pdb
• 分子名称: Protein enabled homolog, (3~{S},6~{S},7~{R},9~{a}~{R})-6-[[(3~{S},6~{R},8~{a}~{S})-1'-[(2~{S})-2-acetamido-3-(2-chlorophenyl)propanoyl]-5-oxidanylidene-spiro[1,2,3,8~{a}-tetrahydroindolizine-6,2'-pyrrolidine]-3-yl]carbonylamino]-7-methyl-5-oxidanylidene-1,2,3,6,7,9~{a}-hexahydropyrrolo[1,2-a]azepine-3-carboxylic acid, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: proline-rich motif, ena/vasp inhibitor, actin, protein-protein interaction, cell adhesion
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13452.50

構造登録者

Barone, M.,Roske, Y. (登録日: 2017-03-01, 公開日: 2017-05-24, 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 (1.15 Å)