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Review
. 2021 Dec 8;10(12):3462.
doi: 10.3390/cells10123462.

Small Endogenous Ligands Modulation of Nerve Growth Factor Bioactivity: A Structural Biology Overview

Francesca Paoletti  1 , Doriano Lamba  2   3
Affiliations
Review

Small Endogenous Ligands Modulation of Nerve Growth Factor Bioactivity: A Structural Biology Overview

Francesca Paoletti et al. Cells. .

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.

Keywords: ATP; bioactivity modulation; lysophospholipids; nerve growth factor; small endogenous ligands; zinc.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the lysophospholipids involved in NGF binding. (A) Lysophosphatidylserine (Lyso-PS). (B) Lysophosphatidylinositol (Lyso-PI). (C) Diacylglycerol (DG). The KD value of the binding of the lysophospholipids to NGF, when available, is reported.
Figure 2
Figure 2
(A) 3D structure of NGF (PDB ID: 6YW8 [5]). The two protomers are colored in cyan and green, respectively. N- and C-termini are labeled. Loops have been labelled according to Ibanez [27]. Two different protein orientations are shown. Figures were produced using PyMOL [28]. (B) Sequence alignment of the NGF of the different species for which a PDB-deposited 3D structure is available. The alignment was performed with ClustalW webserver [29]. UniProt entry numbers are indicated. Loops have been labelled according to Ibanez [27].
Figure 3
Figure 3
Binding sites of mNGF/hNGF/cNGF complexed with DG (A), Lyso-PI (B), Lyso-PS (C), respectively. The ligands and the protein side chains are shown in ball-and-stick representation, with the ligand bonds colored in purple. Hydrogen bonds are shown as green dotted lines, while the spoked arcs represent protein residues making nonbonded (hydrophobic) contacts with the ligand. The 2D ligand–protein interaction diagrams have been produced with LigPlot+ [30].
Figure 4
Figure 4
Binding orientation of ATP on rhNGF. (A,C) Representative poses from MD analysis for Site 1 (A) and Site 2 (B). Cyan and green transparent cartoon: rhNGF protomers; ATP is represented as colored by element (C—green; N—blue; O—red; H—white; P—orange). Residues V20, E55 and F49 showing new NOEs upon ATP binding are labelled and colored by element (C—violet; N—blue; O—red; H—white). Black broken lines represent the distances between HN protons of rhNGF and ATP protons (indicated by a blue arrow). Figures produced using PyMOL [28]. (B,D)—Binding sites of rhNGF complexed with ATP for Site 1 (B) and Site 2 (D), respectively. The ligands and protein side chains are shown in ball-and-stick representation, with the ligand bonds colored in purple. Hydrogen bonds are shown as green dotted lines, while the spoked arcs represent protein residues making nonbonded (hydrophobic) contacts with the ligand. The 2D ligand–protein interaction diagrams have been produced with LigPlot+ [30].
Figure 5
Figure 5
Binding sites of llama NGF complexed with phosphate ion. The binding of phosphate ion with protomer A and B is shown in panels (A,B), respectively. The ligands and protein side chains are shown in ball-and-stick representation, with the ligand bonds colored in purple. Hydrogen bonds are shown as green dotted lines. The 2D ligand–protein interaction diagrams have been produced with LigPlot+ [30].
Figure 6
Figure 6
Mapping of the binding regions of the endogenous small ligands on NGF structure. Schematic drawing of NGF primary structure with indication of secondary structure elements and loops names according to Ibanez [27]. Figure generated using Top Draw sketchpad [66]. The stretches of residues involved in the binding to the different small endogenous ligands are indicated by different color codes. Lyso-PS: blue; Lyso-PI: green; DG: red; ATP: site 1—magenta, Site 2—yellow; PO43−: orange; Zn2+: pink; CS-E: teal.
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