Hidden complexity of α7 nicotinic acetylcholine receptor desensitization revealed by MD simulations and Markov state modeling

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(7)

Published: Feb. 13, 2025

The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in neuronal signaling throughout the nervous system. Its implication neurological disorders and inflammation has spurred development of numerous compounds enhance activation. However, therapeutic potential these been limited by characteristically fast desensitization receptor. Using recent high-resolution structures from cryo-EM, all-atom molecular dynamic simulations augmented Markov state modeling, here we explore mechanism its on allosteric modulation. results provide precise characterization gate illuminate ion-pore opening/closing with agonist bound. In addition, reveal existence short-lived, open-channel intermediate between activated desensitized states rationalizes paradoxical pharmacology L247T mutant may be relevant to type-II This analysis provides interpretation signal transduction regulation receptors.

Language: Английский

Mining the Dynamical Properties of Substrate and FAD Binding Pockets of LSD1: Hints for New Inhibitor Design Direction

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(12), P. 4773 - 4780

Published: June 5, 2024

Lysine-specific demethylase 1 (LSD1), a highly sophisticated epigenetic regulator, orchestrates range of critical cellular processes, holding promising therapeutic potential for treating diverse diseases. However, the clinical research progress targeting LSD1 is very slow. After 20 years research, only one small-molecule drug, BEA-17, degradation and CoREST has been approved by U.S. Food Drug Administration. The primary reason this may be lack abundant structural data regarding its intricate functions. To gain deeper understanding conformational dynamics guide drug design process, we conducted molecular simulations to explore states in apo state under influence cofactors flavin adenine dinucleotide (FAD) CoREST. Our results showed that, across all states, substrate binding pocket exhibited high flexibility, whereas FAD remained more stable. These distinct dynamical properties are essential LSD1's ability bind various substrates while maintaining efficient demethylation activity. Both pockets can enlarged merging with adjacent pockets, although shrink into smaller pockets. new shapes inform inhibitor design, particularly selectively FAD-competitive inhibitors LSD1, given presence numerous FAD-dependent enzymes human body. More interestingly, absence binding, united partitioned conserved residue Tyr761, offering valuable insights that disrupt crucial steric role Tyr761 redox FAD. Additionally, identified positively or negatively correlate which exploited allosteric concurrent inhibitors. reveal as well multiple novel deepen our functions aid rational

Language: Английский

Differential pathogenetic mechanisms of mutations in helix 2 and helix 6 of rhodopsin

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 279, P. 135089 - 135089

Published: Aug. 26, 2024

Variants in rhodopsin (RHO) have been linked to autosomal dominant congenital stationary night blindness (adCSNB), which affects the ability see dim light, and pathogenetic mechanism is still not well understood.In this study we report two novel RHO variants found adCSNB families, p.W265R p.A269V, that map sixth transmembrane domain of protein.We applied silico molecular simulation vitro biochemical studies characterize new compare determinants previously characterized variants, p.G90D p.T94I, second demonstrate W265R A269V cause constitutive activation with light-independent G protein coupling impaired binding arrestin.Differently, G90D T94I are by slow kinetics deactivation.This provides evidence on differential contribution α-helixes six interaction intracellular transducers mutations these helixes result a similar phenotype patients but distinct effects.

Language: Английский