Targeting SxIP-EB1 interaction: An integrated approach to the discovery of small molecule modulators of dynamic binding sites
| Autor: | Andrew J. Carnell, Igor L. Barsukov, Neil G. Berry, T.B. Almeida |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Proline Amino Acid Motifs lcsh:Medicine Plasma protein binding Computational biology macromolecular substances Microtubules Article 03 medical and health sciences 0302 clinical medicine Microtubule Drug Discovery Serine Humans Protein Interaction Domains and Motifs Protein Interaction Maps Binding site Isoleucine lcsh:Science Virtual screening Multidisciplinary Binding Sites Chemistry Binding protein lcsh:R Integrated approach Small molecule 030104 developmental biology 030220 oncology & carcinogenesis lcsh:Q Protein target Microtubule-Associated Proteins Protein Binding |
| Zdroj: | SCIENTIFIC REPORTS Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-12 (2017) |
| Popis: | End binding protein 1 (EB1) is a key element in the complex network of protein-protein interactions at microtubule (MT) growing ends, which has a fundamental role in MT polymerisation. EB1 is an important protein target as it is involved in regulating MT dynamic behaviour, and has been associated with several disease states, such as cancer and neuronal diseases. Diverse EB1 binding partners are recognised through a conserved four amino acid motif, (serine-X-isoleucine-proline) which exists within an intrinsically disordered region. Here we report the use of a multidisciplinary computational and experimental approach for the discovery of the first small molecule scaffold which targets the EB1 recruiting domain. This approach includes virtual screening (structure- and ligand-based design) and multiparameter compound selection. Subsequent studies on the selected compounds enabled the elucidation of the NMR structures of the C-terminal domain of EB1 in the free form and complexed with a small molecule. These structures show that the binding site is not preformed in solution, and ligand binding is fundamental for the binding site formation. This work is a successful demonstration of the combination of modelling and experimental methods to enable the discovery of compounds which bind to these challenging systems. |
| Databáze: | OpenAIRE |
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