Biology subjects

Bermudez, I.

Publications and source records attributed to Bermudez, I..

4 recordsLinked to original sources

bioRxiv2025

How Varenicline Works: Identifying Critical Receptor and Ligand-based Interactions

Approved by the FDA in 2006, varenicline became the first nicotinic-based therapeutic for smoking cessation and has since been used by tens of millions of smokers worldwide. Varenicline works by targeting the 4{beta}2 nicotinic acetylcholine receptor (nAChR), the primary focus for nicotine addiction, where ligand recognition by the receptor triggers ion channel opening. While widely recognized that vareniclines development was rooted in the well-established pharmacology of cytisine, the two compounds display notably different profiles, not only at nAChRs, but also at key off-target sites such as the 5-HT3 serotonin receptor. Despite vareniclines widespread use and proven efficacy as a smoking cessation aid, our knowledge of the precise molecular mechanism underlying its action, particularly the specific receptor-ligand interactions that underpin its functional specificity, remains incomplete. Through a multidisciplinary approach that integrates complementary fields of research, this study reveals the critical receptor-ligand interactions that distinguish varenicline from related nAChR agonists, such as cytisine and nicotine. Our findings reveal previously unrecognized, critical hydrogen bonding interactions within the 4{beta}2 binding sites, specifically involving 4T139, 4T183, and {beta}2S133, that are uniquely and selectively engaged by varenicline. Of these, {beta}2S133 emerged as the pivotal determinant of vareniclines function, with substitution by valine significantly impairing the ligand efficacy. Furthermore, the design and synthesis of novel varenicline analogues shed new light into the functional importance of the ligands quinoxaline moiety, revealing that not just the presence but also the precise positioning of this hydrogen bond acceptor are critical for receptor activation by varenicline. Together, these findings uncover a previously uncharacterized interaction network essential for vareniclines function at 4{beta}2, offering a deeper and more comprehensive framework for understanding its distinct pharmacological profile while expanding our broader understanding of how ligand binding is translated into function in these receptors. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/659675v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@a77e39org.highwire.dtl.DTLVardef@4fec37org.highwire.dtl.DTLVardef@11d26a2org.highwire.dtl.DTLVardef@d35640_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2022

Structural and temporal basis for agonism in the α4β2 nicotinic acetylcholine receptor

Despite decades of study, the structural mechanisms underpinning agonist efficacy in pentameric ligand-gated ion channels remain poorly understood. Here, a combination of extensive equilibrium and dynamical-nonequilibrium molecular dynamics simulations was used to obtain a detailed description of the structural and dynamic changes induced within the human 4{beta}2 nicotinic acetylcholine receptor by a full and a partial agonist, namely acetylcholine and nicotine, and map how these rearrangements propagate within this receptor. These simulations reveal how the agonists modulate the patterns associated with intra and inter-domain communication and the evolution of the agonist-specific structural rearrangements. For the first time, we show that full and partial agonists, although generally using similar routes for through-receptor signal transmission, induce different amplitudes of conformational rearrangements in key functional motifs, thus impacting the rates of signal propagation within the protein. The largest agonist-induced conformational differences are located in the Cys loop, loops C and 1-{beta}1 in the 4 subunit, loops F and {beta}1-{beta}2 in the {beta}2 subunit and in the extracellular selectivity filter.

biochemistry↗

bioRxiv2020

Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors and suggest subtype specificity

Changeux et al. recently suggested that the SARS-CoV-2 spike (S) protein may interact with nicotinic acetylcholine receptors (nAChRs). Such interactions may be involved in pathology and infectivity. Here, we use molecular simulations of validated atomically detailed structures of nAChRs, and of the S protein, to investigate this nicotinic hypothesis. We examine the binding of the Y674-R685 loop of the S protein to three nAChRs, namely the human 4{beta}2 and 7 subtypes and the muscle-like {beta}{gamma}d receptor from Tetronarce californica. Our results indicate that Y674-R685 has affinity for nAChRs and the region responsible for binding contains the PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses. In particular, R682 has a key role in the stabilisation of the complexes as it forms interactions with loops A, B and C in the receptors binding pocket. The conformational behaviour of the bound Y674-R685 region is highly dependent on the receptor subtype, adopting extended conformations in the 4{beta}2 and 7 complexes and more compact ones when bound to the muscle-like receptor. In the 4{beta}2 and {beta}{gamma}d complexes, the interaction of Y674-R685 with the receptors forces the loop C region to adopt an open conformation similar to other known nAChR antagonists. In contrast, in the 7 complex, Y674-R685 penetrates deeply into the binding pocket where it forms interactions with the residues lining the aromatic box, namely with TrpB, TyrC1 and TyrC2. Estimates of binding energy suggest that Y674-R685 forms stable complexes with all three nAChR subtypes. Analyses of the simulations of the full-length S protein show that the Y674-R685 region is accessible for binding, and suggest a potential binding orientation of the S protein with nAChRs.

biochemistry↗

bioRxiv2020

Structural correlates of human muscle nicotinic acetylcholine receptor subunit assembly mediated by δ(+) interface residues

Muscle nicotinic acetylcholine receptors are a class of heteropentameric ligand-gated cation channels with constituent subunits adopting a fixed stoichiometric arrangement. The specific amino acid residues that govern subunit ordering are however, only partially understood. By integrating all-atom molecular dynamics simulations, bioinformatics, two-electrode voltage clamp electrophysiology and 125I--bungarotoxin assays of chimeric nAChR subunits, we identify residues across the extracellular, transmembrane and extended M4 helix of the {delta} subunit that make structural signatures that contribute to intransigent assembly rules. Furthermore, functional differences observed in 2{delta}2{beta} receptors can be rationalized by changes in dynamical behavior that manifest themselves at the agonist binding site.

neuroscience↗