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

• Published in: Biochemical and biophysical research communications 2018-01, Vol.495 (1), p.700-705
• Main Authors: Carleton, Laura A., Chakravarthy, Reka, van der Sloot, Almer M., Mnich, Katarzyna, Serrano, Luis, Samali, Afshin, Gorman, Adrienne M.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Binding Sites; Drug Design; FoldX; GENE MUTATIONS; Mutagenesis, Site-Directed - methods; Nerve Growth Factor - biosynthesis; Nerve Growth Factor - chemistry; Nerve Growth Factor - genetics; NERVES; NGF; p75 neurotrophin receptor (p75NTR); PAIN; PC12 Cells; Protein Binding; Protein Engineering - methods; Rats; Receptors, Nerve Growth Factor - chemistry; Receptors, Nerve Growth Factor - metabolism; Structure-Activity Relationship; TrkA
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.11.003

Nerve growth factor (NGF) is the prototypic member of the neurotrophin family and binds two receptors, TrkA and the 75 kDa neurotrophin receptor (p75NTR), 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 p75NTR. Of these, the I31R NGF variant exhibited specific binding to p75NTR. The generation of this NGF variant with selective affinity for p75NTR 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. •We characterized NGF variants predicted by FoldX protein design algorithm to have an altered binding to TrkA and p75NTR.•I31 was identified as a key residue within NGF that distinguishes between TrkA and p75NTR binding.•The I31R NGF selectively binds and activates p75NTR, while it did not exhibit the biological activity at TrkA receptor.