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

Laura A. Carleton; Reka Chakravarthy; Almer M. van der Sloot; Katarzyna Mnich; Luis Serrano; Afshin Samali; Adrienne M. Gorman

doi:10.1016/j.bbrc.2017.11.003

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

Laura A. Carleton
, Reka Chakravarthy
, Almer M. van der Sloot
, Katarzyna Mnich
, Luis Serrano
, Afshin Samali
, Adrienne M. Gorman

Cellular & Molecular Medicine

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

13 Citations (Scopus)

Abstract

Nerve growth factor (NGF) is the prototypic member of the neurotrophin family and binds two receptors, TrkA and the 75 kDa neurotrophin receptor (p75^NTR), 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^NTR. Of these, the I31R NGF variant exhibited specific binding to p75^NTR. The generation of this NGF variant with selective affinity for p75^NTR 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.

Original language	English
Pages (from-to)	700-705
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	495
Issue number	1
DOIs	https://doi.org/10.1016/j.bbrc.2017.11.003
Publication status	Published - 1 Jan 2018

Keywords

FoldX
NGF
TrkA
p75 neurotrophin receptor (p75)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbrc.2017.11.003

Cite this

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title = "Generation of rationally-designed nerve growth factor (NGF) variants with receptor specificity",

abstract = "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.",

keywords = "FoldX, NGF, TrkA, p75 neurotrophin receptor (p75)",

author = "Carleton, \{Laura A.\} and Reka Chakravarthy and \{van der Sloot\}, \{Almer M.\} and Katarzyna Mnich and Luis Serrano and Afshin Samali and Gorman, \{Adrienne M.\}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

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doi = "10.1016/j.bbrc.2017.11.003",

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AU - Carleton, Laura A.

AU - Chakravarthy, Reka

AU - van der Sloot, Almer M.

AU - Mnich, Katarzyna

AU - Serrano, Luis

AU - Samali, Afshin

AU - Gorman, Adrienne M.

PY - 2018/1/1

Y1 - 2018/1/1

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AB - 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.

KW - FoldX

KW - NGF

KW - TrkA

KW - p75 neurotrophin receptor (p75)

UR - https://www.scopus.com/pages/publications/85033795307

U2 - 10.1016/j.bbrc.2017.11.003

DO - 10.1016/j.bbrc.2017.11.003

M3 - Article

SN - 0006-291X

VL - 495

SP - 700

EP - 705

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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