6RCJ
ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-15]-OMe
Summary for 6RCJ
Entry DOI | 10.2210/pdb6rcj/pdb |
Related | 6RCF |
Descriptor | Protein enabled homolog, methyl 2-[(3~{a}~{R},6~{R},8~{a}~{S})-1-[(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]carbonyl-6-ethyl-8-oxidanylidene-3,3~{a},6,8~{a}-tetrahydro-2~{H}-pyrrolo[2,3-c]azepin-7-yl]ethanoate, NITRATE ION, ... (5 entities in total) |
Functional Keywords | proline-rich motif, ena/vasp inhibitor, actin, protein-protein interaction, cell adhesion |
Biological source | Homo sapiens (Human) |
Total number of polymer chains | 1 |
Total formula weight | 13538.59 |
Authors | Barone, M.,Roske, Y. (deposition date: 2019-04-11, release date: 2020-05-13, Last modification date: 2024-01-31) |
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 (1.35 Å) |
Structure validation
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