Sandbox Reserved 1110

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This Sandbox is Reserved from 25/11/2019, through 30/9/2020 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1091 through Sandbox Reserved 1115.
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Contents

5LSD

5LSD is the recombinant mouse Nerve Growth Factor (NGF), that does not bind to any ligand. Therefore it allows conclusions on the features of its binding loops. Through 5LSD, 3 questions can be targeted: (i) how is the NGF N-terminus structured in the absence of ligands? (ii) how flexible/rigid are the loops and how does their dynamics may reflect on the overall structural plasticity of mature NGF? (iii) how much do the loops contribute to antibody recognition?[1]

Structure

In the absence of partners, the NGF N-terminus has a strong tendency to fold into a helix. This challenges the current view that this region is unstructured. The loops, especially II and V, and the C-terminus are relatively more flexible (showing hetNOE values lower than the average (0.7)) than the more rigid β-sheet regions. The loop variations are however relatively small compared to the flexibility of the N- and C-termini, which indicates that the loops are plastic but not flexible. [2]


The neurotrophin family

Disease and use in Biotechnologies/ Relevance link title

As NGF is the prototype of the neurotrophin family, a better understanding of NGF could lead to a better understanding of the whole family. A better knowledge of NGF, i.e. through 5LSD, is supportive. The NMR structure of 5LSD lead to the conclusion that NGF has long plastic but relatively rigid loops, which is of crucial importance for future drug design.[3]

Differences and importance of unbound feature

In the crystal structures of free and bound NGF, the conformation of loop II Shows high plasticity. An Overall Opening of the structure occurs for accomodation of small ligands.



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References

  1. ↑ Paoletti F, de Chiara C, Kelly G, Covaceuszach S, Malerba F, Yan R, Lamba D, Cattaneo A, Pastore A. Conformational Rigidity within Plasticity Promotes Differential Target Recognition of Nerve Growth Factor. Front Mol Biosci. 2016 Dec 26;3:83. doi: 10.3389/fmolb.2016.00083. eCollection, 2016. PMID:28083536 doi:http://dx.doi.org/10.3389/fmolb.2016.00083
  2. ↑ Paoletti F, de Chiara C, Kelly G, Covaceuszach S, Malerba F, Yan R, Lamba D, Cattaneo A, Pastore A. Conformational Rigidity within Plasticity Promotes Differential Target Recognition of Nerve Growth Factor. Front Mol Biosci. 2016 Dec 26;3:83. doi: 10.3389/fmolb.2016.00083. eCollection, 2016. PMID:28083536 doi:http://dx.doi.org/10.3389/fmolb.2016.00083
  3. ↑ Bannwarth B, Kostine M. Targeting nerve growth factor (NGF) for pain management: what does the future hold for NGF antagonists? Drugs. 2014 Apr;74(6):619-26. doi: 10.1007/s40265-014-0208-6. PMID:24691709 doi:http://dx.doi.org/10.1007/s40265-014-0208-6
[1]Paoletti F, de Chiara C, Kelly G, Covaceuszach S, Malerba F, Yan R, Lamba D, Cattaneo A, Pastore A. Conformational Rigidity within Plasticity Promotes Differential Target Recognition of Nerve Growth Factor. Front Mol Biosci. 2016 Dec 26;3:83. doi: 10.3389/fmolb.2016.00083. eCollection, 2016. PMID:28083536 doi:http://dx.doi.org/10.3389/fmolb.2016.00083.

[2]Tiveron C1, Fasulo L, Capsoni S, Malerba F, Marinelli S, Paoletti F, Piccinin S, Scardigli R, Amato G, Brandi R, Capelli P, D'Aguanno S, Florenzano F, La Regina F, Lecci A, Manca A, Meli G, Pistillo L, Berretta N, Nisticò R, Pavone F, Cattaneo A. ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice. Cell Death Differ. 2013 Aug;20(8):1017-30. doi: 10.1038/cdd.2013.22. [3] B. A. Mysona, S. Matragoon, M. Stephens, I. N. Mohamed, A. Farooq, M. L. Bartasis, A. Y. Fouda, A. Y. Shanab, D. G. Espinosa-Heidmann, 2 and A. B. El-Remessy Imbalance of the Nerve Growth Factor and Its Precursor as a Potential Biomarker for Diabetic Retinopathy. Biomed Res Int. 2015; 2015: 571456. doi: 10.1155/2015/571456. [4] McDonald NQ, Lapatto R, Murray-Rust J, Gunning J, Wlodawer A, Blundell TL. New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor. Nature. 1991 Dec 5;354(6352):411-4. doi: 10.1038/354411a0. [5]M. Pattarawarapan and K. Burgess (2003) Molecular basis of Neurotrophin-Receptor Interactions. Journal of Medicinal Chemistry 46, 5277-5291. [6] M. Bibel and Y.-A. Barde (2000) Neurotrophins: Key Regulators of Cell Fate and Cell Shape in the Vertebrate Nervous System. Genes and Development 14, 2919-2937

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