Biology subjects

Hazarika, S.

Publications and source records attributed to Hazarika, S..

3 recordsLinked to original sources

bioRxiv2024

Molecular Dynamics Simulations Reveal the Importance of Non-Native Interactions in Modulating the Inactive to Active Conformational Transition in Progesterone Receptor

Nuclear receptors are a family of transcription factors that activate respective genes when bound to specific ligands. Certain ligands induce conformational changes in the receptor which helps them recruit co-activators. The conformational changes induced by these ligands conformationally transition inactive conformation into an active conformation by changing the orientation of the C-terminal helix (H12). Despite their immense physiological importance, very few questions have been solved about the kinetics and the molecular mechanism of this transition from the inactive to active conformation. In this study, we have used extensive unbiased atomistic molecular dynamics simulations of Progesterone receptor bound to a partial agonist asoprisnil to investigate these two questions. Two different crystal structures for this complex provide us with a unique opportunity to study the conformational transition at the molecular level. Apart from elucidating several important dynamical information from these simulations, we used Markov state modeling to calculate the rate of the transition between the inactive and active-like states. More importantly, we have also shown the importance of non-native interactions in this conformational transition, which were seen to be formed during the transition from inactive to active-like conformation but not present in the active conformation itself. Apart from contributing to our fundamental understanding about the structure and dynamics of nuclear receptor at the molecular level, this study might be able to contribute to the larger problem of protein-folding itself.

biophysics↗

bioRxiv2024

The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome

PurposeVascular Ehlers Danlos Syndrome (vEDS) is a connective tissue disorder caused by COL3A1 mutations for which there are no treatments due to a limited understanding of underlying mechanisms. We aimed to address this critical knowledge gap, focusing on collagen folding, to establish if targeting protein folding represents a potential therapeutic approach. MethodsWe performed a mechanistic analysis of two novel COL3A1 glycine mutations, G189S and G906R, using primary patient fibroblast cultures, and performed pre-clinical proof-of-concept treatments using FDA-approved chemical chaperones targeting protein folding and/or degradation. ResultsCOL3A1 mutations caused secretion of misfolded collagen III and intracellular collagen retention, leading to matrix defects and endoplasmic reticulum (ER) stress, with increased severity for the more C-terminal mutation. Promoting ER protein folding capacity through the chemical chaperone 4-phenylbutyric acid rescued the ER stress, thermostability of secreted collagen, matrix defects and apoptosis. Optimising treatment duration and dosage helped overcome allele-dependent treatment efficacy. In contrast, protein degradation alone or combined with targeting protein folding did not increase efficacy. ConclusionER stress is a molecular mechanism in vEDS that can be influenced by the position of COL3A1 mutation, and promoting protein folding is a putative mechanism-based therapeutic approach that can rescue intra- and extracellular defects.

genetics↗

bioRxiv2024

Describing interdomain communication and allostery in full-length FXR

Nuclear receptors are ligand-induced transcription factors that bind directly to target genes and regulate their expression. Ligand binding initiates conformational changes that propagate to other domains, allosterically regulating their activity. The nature of this interdomain communication in nuclear receptors is poorly understood, largely owing to the difficulty of experimentally characterizing full-length structures. We have applied computational modeling approaches to describe and study the structure of the full length farnesoid X receptor (FXR), approximated by the DNA binding domain (DBD) and ligand binding domain (LBD) connected by the flexible hinge region. Using extended molecular dynamics simulations (> 10 microseconds) and enhanced sampling simulations, we provide evidence that ligands selectively induce domain rearrangement, leading to interdomain contact. We use protein-protein interaction assays to provide experimental evidence of these interactions, identifying a critical role of the hinge in mediating interdomain contact. Our results illuminate previously unknown aspects of interdomain communication in FXR and provide a framework to enable characterization of other full length nuclear receptors.

biochemistry↗