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A modular toolkit to inhibit proline-rich motif-mediated protein-protein interactions

Item Type:Article
Title:A modular toolkit to inhibit proline-rich motif-mediated protein-protein interactions
Creators Name:Opitz, R. and Mueller, M. and Reuter, C. and Barone, M. and Soicke, A. and Roske, Y. and Piotukh, K. and Huy, P. and Beerbaum, M. and Wiesner, B. and Beyermann, M. and Schmieder, P. and Freund, C. and Volkmer, R. and Oschkinat, H. and Schmalz, H.G. and Kuehne, R.
Abstract:Small-molecule competitors of protein-protein interactions are urgently needed for functional analysis of large-scale genomics and proteomics data. Particularly abundant, yet so far undruggable, targets include domains specialized in recognizing proline-rich segments, including Src-homology 3 (SH3), WW, GYF, and Drosophila enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Here, we present a modular strategy to obtain an extendable toolkit of chemical fragments (ProMs) designed to replace pairs of conserved prolines in recognition motifs. As proof-of-principle, we developed a small, selective, peptidomimetic inhibitor of Ena/VASP EVH1 domain interactions. Highly invasive MDA MB 231 breast-cancer cells treated with this ligand showed displacement of VASP from focal adhesions, as well as from the front of lamellipodia, and strongly reduced cell invasion. General applicability of our strategy is illustrated by the design of an ErbB4-derived ligand containing two ProM-1 fragments, targeting the yes-associated protein 1 (YAP1)-WW domain with a fivefold higher affinity.
Keywords:Ena, VASP, Protein-Protein Interaction, Actin Cytoskeleton, Cell Migration, Animals, Drosophila Melanogaster
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:112
Number:16
Page Range:5011-5016
Date:21 April 2015
Official Publication:https://doi.org/10.1073/pnas.1422054112
PubMed:View item in PubMed

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