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Luba Tchertanov

CMLA ENS Cachan, France

Title: How Conformational Dynamics Descriptors may help in remodeling of allosteric Regulation in Proteins

Biography

Biography: Luba Tchertanov

Abstract

Allostery controls nearly all biological processes, and it has been declared Monod to be “the second secrete of life” after the genome. This universal phenomenon in nature represents a target response on a perturbation (e.g. a ligand binding) leading to a functional change at the target through alteration of the structure or dynamics. Such an event can be described in terms of a large-scale transmission of information between residues. This concept is the cornerstone of our method MONETA that delivers descriptor encoding of the communication network in a protein [1]. Using MONETA, we described the allosteric regulation of several proteins involved in cell signalling. Studying the receptors tyrosine kinases (RTKs), KIT and CSF-1R, and their numerous clinically-relevant mutants, we showed that the allosteric communications between the major regulating fragments in the native proteins were disrupted by the gain-of-function mutations [2-4]. The diverging impact of equivalent mutations on communication in homologue RTKs permits us to distinguish between the mutation-induced effects that lead to the constitutive activation of KIT and the mutation-induced effects promoted the resistance in CSF-1R. In STAT5s, RTK downstream signalling proteins, we showed the sequence-dependent asymmetry in the STAT5s’ communications and their different responses to phosphorylation [5]. Our recent study provided a fascinating illustration of how the binding of agonist ligands controls intrinsic conformational dynamics in human NMDA receptors that stabilize the channel opening. The allosteric binding sites, which were identified by a pockets search at the proteins surface adjacent to the communication pathway (Figure 1), may constitute valid targets for the development of inhibitors able to modulate the function-related communication properties of a protein. Such communication-inspired and communication-targeted modulation may selectively block several activation or post-transduction processes. Our work opens the way to novel and rational strategies for the definition of targets, and the development of efficient target-specific inhibitors.

References:

  1. Allain A, Chauvot de Beauchêne I, Langenfeld F, Guarracino Y, Laine E, Tchertanov L. (2014). Allosteric Pathway Identification through Network Analysis from Molecular Dynamics Simulations to Interactive 2D and 3D Graphs. Faraday Disc., 169, 1-18.
  2. Chauvot de Beauchêne I, Alain A, Panel N, Laine E, Trouvé A, Dubreuil P. and Tchertanov L. (2014). Oncogenic mutations of KIT receptor differentially modulate tyrosine kinase activity and drug susceptibility. PLOS Comput. Biol.;10(7):e1003749.
  3. Da Silva Figueiredo Celestino Gomes P, Chauvot de Beauchêne I, Panel N, Pascutti P, Solary E, Tchertanov L. Insight on Mutation-Induced Resistance from Molecular Dynamics Simulations of Wild-type and mutated CSF-1R and KIT. (2016) PLoS ONE.11(7):e0160165.
  4. Chauvot de Beauchêne I, Tchertanov L. (2016). How Missense Mutations in Receptors Tyrosine Kinases impact Constitutive Activity and alternate Drug Sensitivity: Insights from Molecular Dynamics Simulations. Invited Research highlight for Receptors & Clinical Investigation. Vol.3, e1372.
  5. Langenfeld F, Guarracino Y, Arock M, Trouvé A,Tchertanov L. (2015). How intrinsic molecular dynamics controls intramolecular communication in Signal Transducers and Activators of Transcription Factor STAT5. PLOS ONE. Dec 30;10(12):e0145142.