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Volume 10, Issue 8 (Suppl) J Proteomics Bioinform, an open access journal
ISSN: 0974-276X Structural Biology 2017
September 18-20, 2017
9th International Conference on
Structural Biology
September 18-20, 2017 Zurich, Switzerland
How conformational dynamics descriptors may help in remodeling of allosteric regulation in proteins
Luba Tchertanov
CMLA - ENS Cachan, France
Allostery controls nearly all biological processes, and it has been declared by 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. 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. 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. Our recent study provided a fascinating illustration of how the binding of agonist
ligands controls intrinsic conformational dynamics in humanNMDA receptors that stabilize the channel opening.The allosteric
binding sites, which were identified by a pocket search at the proteins surface adjacent to the communication pathway, 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.
Biography
Luba Tchertanov is a Research Director at CNRS-France, leader of the Bioinformatics, Molecular Dynamics and Modeling (BiMoDyM) team in Centre Mathématiques
et leurs Applications (CMLA-CNRS) at the Ecole Normale Supérieure (ENS) de Cachan. She has multidisciplinary high-level skills, with extensive experience in
structural biology, molecular modelling and numerical simulation (more than 100 papers in peer-reviewed journals). She coordinated or contributed as team-leader
to different research projects (CEE, ANR, Fondation de France, OSEO, SIDACTION) and industrial contracts (LIPHATECH, the SERVIER Institute, the Pierre
FABRE Laboratory, UNILIVER). The research topics are focused on exploration of protein structure–dynamics–function relations. In particular, she is working at
the mechanisms of the receptors activation, the mechanisms of resistance to inhibitors, the conformational plasticity and dynamics of inter-molecular interactions
and molecular recognition. She is specifically interested in description of allosteric regulation at an atomistic level. Important part of research is dedicated to the
development of new methodology and computing tools for description of proteins dynamics.
Luba Tchertanov et al., J Proteomics Bioinform 2017, 10:8(Suppl)
DOI: 10.4172/0974-276X-C1-0100
Figure1: Communication pathway in STAT5 (left)
and location of pockets at the protein surface
adjacent to the communication pathway (right).