Generation of rationally-designed nerve growth factor (NGF) variants with receptor specificity.

TitleGeneration of rationally-designed nerve growth factor (NGF) variants with receptor specificity.
Publication TypeJournal Article
Year of Publication2018
AuthorsCarleton LA, Chakravarthy R, van der Sloot AM, Mnich K, Serrano L, Samali A, Gorman AM
JournalBiochem Biophys Res Commun
Date Published2018 01 01
KeywordsAnimals, Binding Sites, Drug Design, Mutagenesis, Site-Directed, Nerve Growth Factor, PC12 Cells, Protein Binding, Protein Engineering, Rats, Receptors, Nerve Growth Factor, Structure-Activity Relationship

Nerve growth factor (NGF) is the prototypic member of the neurotrophin family and binds two receptors, TrkA and the 75 kDa neurotrophin receptor (p75), through which diverse and sometimes opposing effects are mediated. Using the FoldX protein design algorithm, we generated eight NGF variants with different point mutations predicted to have altered binding to TrkA or p75. Of these, the I31R NGF variant exhibited specific binding to p75. The generation of this NGF variant with selective affinity for p75 can be used to enhance understanding of neurotrophin receptor imbalance in diseases and identifies a key targetable residue for the development of small molecules to disrupt binding of NGF to TrkA with potential uses in chronic pain.

Alternate JournalBiochem. Biophys. Res. Commun.
PubMed ID29108999