6evi Citations

Targeting SxIP-EB1 interaction: An integrated approach to the discovery of small molecule modulators of dynamic binding sites.

OpenAccess logo Sci Rep 7 15533 (2017)
Cited: 6 times
EuropePMC logo PMID: 29138501

Abstract

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.

Articles - 6evi mentioned but not cited (2)

  1. The novel antibiotic rhodomyrtone traps membrane proteins in vesicles with increased fluidity. Saeloh D, Tipmanee V, Jim KK, Dekker MP, Bitter W, Voravuthikunchai SP, Wenzel M, Hamoen LW. PLoS Pathog 14 e1006876 (2018)
  2. Targeting SxIP-EB1 interaction: An integrated approach to the discovery of small molecule modulators of dynamic binding sites. Almeida TB, Carnell AJ, Barsukov IL, Berry NG. Sci Rep 7 15533 (2017)


Articles citing this publication (4)

  1. Exponential consensus ranking improves the outcome in docking and receptor ensemble docking. Palacio-Rodríguez K, Lans I, Cavasotto CN, Cossio P. Sci Rep 9 5142 (2019)
  2. SxIP binding disrupts the constitutive homodimer interface of EB1 and stabilizes EB1 monomer. Ayyappan S, Dharan PS, Krishnan A, Marira RR, Lambert M, Manna TK, Vijayan V. Biophys J 120 2019-2029 (2021)
  3. ADNP dysregulates methylation and mitochondrial gene expression in the cerebellum of a Helsmoortel-Van der Aa syndrome autopsy case. D'Incal C, Van Dijck A, Ibrahim J, De Man K, Bastini L, Konings A, Elinck E, Gozes L, Marusic Z, Anicic M, Vukovic J, Van der Aa N, Mateiu L, Vanden Berghe W, Kooy RF. Acta Neuropathol Commun 12 62 (2024)
  4. Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis. Marchal GA, Galjart N, Portero V, Remme CA. Cardiovasc Res 119 1461-1479 (2023)