5NBX
ENAH EVH1 in complex with Ac-[2-Cl-F]-PP-[ProM-9]-OH
Summary for 5NBX
Entry DOI | 10.2210/pdb5nbx/pdb |
Descriptor | Protein enabled homolog, ACY-2L5-PRO-PRO-8SN, BROMIDE ION, ... (4 entities in total) |
Functional Keywords | proline-rich motif, ena/vasp inhibitor, actin, protein-protein interaction, cell adhesion |
Biological source | Homo sapiens (human) More |
Total number of polymer chains | 4 |
Total formula weight | 26640.81 |
Authors | Barone, M.,Roske, Y. (deposition date: 2017-03-02, release date: 2018-03-21, Last modification date: 2024-02-07) |
Primary citation | 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 Cited by 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: 33184177DOI: 10.1073/pnas.2007213117 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.65 Å) |
Structure validation
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