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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
Allosteric control of transcription regulation by nuclear receptors: An integrative structural biology
approach
Dino Moras
Institut de Génétique et de Biologie Moléculaire et Cellulaire, France
Nuclear hormone receptors interact with corepressors, coactivators and other protein cofactors to regulate signal
transduction of the basal transcriptional machinery. Most NRs are known to function as dimers and except for the group
of oxosteroid receptors (AR, GR, MR, PR) all structural data point to a conserved interface for the ligand binding domains
(LBDs) dimers. Allosteric mechanisms control the sequential and ordered binding of nuclear receptors to the various protein
effectors and target DNA. The binding of ligands induces structural transitions in the LBDs leading to the release of the
corepressors and their replacement by cofactors. The LBD swallows the ligand and shields it from the solvent by closing
the pocket with the C-terminal peptide. The agonist/antagonist character of the ligand is then essentially controlled by the
position of helix H12 and the stability of the complex. Ligands are modulators of the activation process, their potency being
defined by the fraction of time spent in the active conformation. Crystal structures of DNA binding domains (DBDs) bound
to different response elements also support the proposal of DNA being an allosteric effector. The architectures of full length
receptors bound to DNA fragments and cofactors have been determined by crystallography and in solution using integrative
approaches. The later combine structural small angle diffraction methods by X-Rays (SAXS) and neutrons (SANS), optical
techniques like FRET with labelled molecules and single particle electron microscopy (cryo-EM). Some common features
emerge that rationalize the key role of DNA. The recent advances in cryo-EM allow solution structures determination at near
atomic resolution. Conformational equilibrium of NRs in complex with various cofactors are also accessible.
Biography
Dino Moras has completed his Graduation in Chemistry at the University of Strasbourg. While pursuing Post-doc with M G Rossmann, he has contributed to the
concept of nucleotide binding domain known as the 'Rossmann fold'. His main scientific contributions are in structural biology, related to the expression of the
genetic information: translation of the genetic code by aminoacyl-tRNA synthetases: discovery of the partition of aaRS in two classes and first crystal structure of
a class II tRNA-aaRS complex and transcription regulation by Nuclear Receptors: the first crystal structures of the ligand binding domains of two NRs (RXR and
RAR) in their apo and liganded form respectively. Presently, his focus is on the molecular mechanisms of regulation using integrative structural biology approaches.
Dino Moras, J Proteomics Bioinform 2017, 10:8(Suppl)
DOI: 10.4172/0974-276X-C1-0100