Structure-based synthetic mimicry of discontinuous protein binding sites: inhibitors of the interaction of Mena EVH1 domain with proline-rich ligands.
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AbstractThe Mena EVH1 domain, a protein-interaction module involved in actin-based cell motility, recognizes proline-rich ligand motifs, which are also present in the sequence of the surface protein ActA of Listeria monocytogenes. The interaction of ActA with host Mena EVH1 enables the bacterium to actively recruit host actin in order to spread into neighboring cells. Based on the crystal structure of Mena EVH1 in complex with a polyproline peptide ligand, we have generated a range of assembled peptides presenting the Mena EVH1 fragments that make up its discontinuous binding site for proline-rich ligands. Some of these peptides were found to inhibit the interaction of Mena EVH1 with the ligand pGolemi. One of them was further characterized at the level of individual amino acid residues; this yielded information on the contribution of individual positions of the peptides to the interaction with the ligand and identified sites for future structure optimization.
CitationChembiochem 2006, 7(8):1258-64
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- The solution structure of pGolemi, a high affinity Mena EVH1 binding miniature protein, suggests explanations for paralog-specific binding to Ena/VASP homology (EVH) 1 domains.
- Authors: Link NM, Hunke C, Mueller JW, Eichler J, Bayer P
- Issue date: 2009 May-Jun
- A novel proline-rich motif present in ActA of Listeria monocytogenes and cytoskeletal proteins is the ligand for the EVH1 domain, a protein module present in the Ena/VASP family.
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- Aromatic and basic residues within the EVH1 domain of VASP specify its interaction with proline-rich ligands.
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- Issue date: 1999 Jul 1
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- Issue date: 2003 Sep 19