Abstract
Experiments with cell cultures and animal models have provided solid support for the assumption that Nerve Growth Factor (NGF) plays a key role in the regulation of neuronal cell survival and death. Recently, endogenous ligands have been proposed as physiological modulators of NGF biological activity as part of this regulatory cascade. However, the structural and mechanistic determinants for NGF bioactivity remain to be elucidated. We recently unveiled, by an integrated structural biology approach, the ATP binding sites of NGF and investigated the effects on TrkA and p75NTR receptors binding. These results pinpoint ATP as a genuine endogenous modulator of NGF signaling, paving the way to the characterization of not-yet-identified chemical diverse endogenous biological active small molecules as novel modulators of NGF. The present review aims at providing an overview of the currently available 3D structures of NGF in complex with different small endogenous ligands, featuring the molecular footprints of the small molecules binding. This knowledge is essential for further understanding the functional role of small endogenous ligands in the modulation of neurotrophins signaling in physiological and pathological conditions and for better exploiting the therapeutic potentialities of NGF.
Highlights
The nerve growth factor (NGF) was the first identified and the structurally and functionally best characterized member of the neurotrophin (NT) family [1]
This review aims to provide an up-to-date analysis of the available 3D structural data on the binding of NGF to small endogenous ligands, with the further intention of identifying common features that are likely to contribute to the binding to molecular surfaces as well as to specific binding pockets, which might be exploited by further biological and pharmacological studies
Surface Plasmon Resonance (SPR) analysis confirmed that Zn2+ markedly affected Adenosine-5 -Triphosphate (ATP) binding to recombinant human NGF (rhNGF). 1D 1H STD-Nuclear Magnetic Resonance (NMR) experiments were used to determine the binding epitope of ATP when bound to rhNGF in the presence of either Mg2+ or Zn2+ ions
Summary
The nerve growth factor (NGF) was the first identified and the structurally and functionally best characterized member of the neurotrophin (NT) family [1]. This review aims to provide an up-to-date analysis of the available 3D structural data on the binding of NGF to small endogenous ligands, with the further intention of identifying common features that are likely to contribute to the binding to molecular surfaces as well as to specific binding pockets, which might be exploited by further biological and pharmacological studies. It is out of the scope of this review the description of the binding of non-endogenous agonists/antagonists small molecules to NGF.
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