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- W128149142 abstract "The EHD1 protein coordinates the expression of surface proteins, such as β1 integrins, that are highly expressed in our human squamous cell carcinoma (SCC) cell line. EHD1 mediates its effects via its Eps15-homology (EH) domain that binds proteins containing an NPF sequence motif. This motif forms a β-turn when bound to the EH domain. Since cyclization promotes turn formation, we asked to what extent constraining a linear NPF peptide promotes turn formation and high affinity. We designed a cyclized NPF peptide using a model of an EH domain-NPF complex. Linear and cyclized peptides were synthesized, affinities were measured and NMR structures were determined. Head-to-tail cyclization increased binding affinity about 5-fold (Kd, linear=4.7 μM vs. Kd, cyclic=1.0±0.2 μM). Although the linear peptide showed cis-trans isomerization and poor chemical shift dispersion in NMR spectra, the cyclized peptide adopted a single conformation and higher chemical shift dispersion. Cyclization clearly improves the structure and binding affinities of peptide-based inhibitors of EHD1 EH domains. We are currently testing whether cyclization improves stability and cell penetration, which would permit the use of EH domain ligands as a novel approach to reducing β1 integrin levels on SCC tumor cells and inhibit disease progression. Supported by a “Tufts Collaborates!” grant (A.A-H. and J.D.B.) and DP2OD007303 (J.A.K.)" @default.
- W128149142 created "2016-06-24" @default.
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- W128149142 date "2013-04-01" @default.
- W128149142 modified "2023-10-16" @default.
- W128149142 title "Design and Characterization of an EHD1 Inhibitor" @default.
- W128149142 doi "https://doi.org/10.1096/fasebj.27.1_supplement.1015.8" @default.
- W128149142 hasPublicationYear "2013" @default.
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