@article{González-Avendaño2026,

title = {Computational Mapping and Targeting of BK Channel Protein–Protein Interactions in Breast Cancer},

author = {Mariela González-Avendaño and Roberto Rosales-Rojas and Ariela Vergara-Jaque },

doi = {10.1021/acs.jcim.6c00191},

year  = {2026},

date = {2026-03-17},

abstract = {Large-conductance Ca2+-activated potassium (BK) channels are widely expressed across human tissues and play fundamental roles in the regulation of diverse cellular processes. Dysregulation of BK channel expression or activity has been implicated in multiple pathological conditions, including cancer, where BK channel overexpression is associated with enhanced tumor cell proliferation and altered cellular dynamics. In this study, we present an integrative computational framework to identify, structurally characterize, and rationally target BK channel-associated protein–protein interactions (PPI) in breast cancer. RNA-seq differential expression analysis revealed significant overexpression of KCNMA1 in estrogen-sensitive breast cancer cells, supporting a central role for BK channels in tumor-associated phenotypes. By integrating transcriptomic data with curated interaction databases and PPI prediction methods, we constructed a breast cancer-specific interaction network centered on BK and identified ACTG2, LINGO1, and RAB4A as high-confidence interaction partners. Structural modeling and coarse-grained molecular dynamics simulations revealed stable, partner-specific interaction interfaces between BK and each interactor, identifying key residues governing complex formation. Building on these results, we present the first computational structural model of the BK-LINGO1 complex, which reveals a predominantly hydrophobic transmembrane interface consistent with the established role of LINGO1 as a regulatory accessory subunit. Leveraging this PPI interface, we designed peptide-based modulators using a structure-guided approach and identified peptide variants with enhanced conformational stability and favorable binding energetics. Overall, our work establishes a robust computational framework for mapping BK channel protein–protein interactions in breast cancer and demonstrates the feasibility of targeting these interactions through rational peptide design, opening new opportunities for the selective modulation of BK channel function in cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Peña-Vilches2026,

title = {Identification of 14-3-3 Proteins as Binding Partners of TRP Channels},

author = {Nicolás Peña-Vilches and Mariela González-Avendaño and Nicole Soto-García and Diego Maureira and Ian Silva and Javiera Avilés and Elías Manríquez-Benítez and Exequiel Medina and Oscar Cerda and Pablo Galaz-Davison and Ariela Vergara-Jaque},

doi = {10.1021/acs.jcim.6c00092},

year  = {2026},

date = {2026-03-16},

abstract = {Transient receptor potential (TRP) channels are regulated by a diverse network of intracellular partners that govern their trafficking, stability, and functional expression at the plasma membrane. Here, we present a comprehensive and integrative characterization of 14-3-3 proteins as conserved binding partners of TRP channels. Leveraging the extensive structural repertoire of 14-3-3 complexes resolved to date, we combined large-scale sequence and structural analyses with molecular docking, coevolutionary inference, machine learning-based predictions, atomistic simulations, and targeted experimental validation to elucidate the molecular principles underlying TRP-14-3-3 recognition. Integration of these approaches into a unified consensus scoring framework revealed recurrent, solvent-exposed cytoplasmic motifs across the TRP channel family with a high propensity for 14-3-3 binding. Focusing on the TRPM4-14-3-3γ interaction, we identified an N-terminal cytoplasmic region of the channel as the primary 14-3-3 binding hotspot. Structural modeling and molecular dynamics simulations revealed a stable electrostatically driven interface, which was experimentally validated by fluorescence anisotropy assays. Moreover, biochemical and functional analyses demonstrated that TRPM4 interacts not only with 14-3-3γ but also with 14-3-3η, leading to a reduced channel-mediated sodium influx. Together, these findings establish 14-3-3 proteins as general and evolutionarily conserved regulators of TRP channels and provide a broadly applicable framework for identifying transient protein–protein interactions relevant to TRP channel dysregulation in disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Maureira2026,

title = {A KCNC1 variant linked to Rett syndrome disrupts ER to Golgi trafficking of Kv3.1 channel},

author = {Diego Maureira and Carla Rubilar and Joaquín López and Paola Santander and Hans Moldenhauer and Ian Silva and Pablo Cruz and Denise Riquelme and Javiera Baeza and Wendy González and Patricio Orio and Evrim Servili and Mónica Troncoso and Elías Leiva-Salcedo and Oscar Cerda},

doi = { 10.1073/pnas.2424514123},

year  = {2026},

date = {2026-03-12},

abstract = {Intrinsic neuronal excitability, defined by the balance between input and output signals, is crucial to neural function, and its disruption underlies various neurological diseases. Kv3.1 channels, encoded by KCNC1, are essential for high-frequency action potential firing. Variants in these channels are associated with several subtypes of epilepsy. We report a patient with developmental regression and epilepsy, meeting Rett syndrome criteria, who carries a KCNC1 variant encoding the S474C substitution in Kv3.1 (Kv3.1S474C). Electrophysiological and biochemical assays reveal that Kv3.1S474C reduces channel presence in the plasma membrane and is retained in the endoplasmic reticulum. In murine primary cortical neuron cultures expressing Kv3.1S474C, we observed reduced neuronal firing frequency and exclusion of the channel from the axon initial segment. Consistently, we found a decreased firing frequency using a conductance-based computational neuronal model. In summary, this study identifies a link between a KCNC1 variant and Rett syndrome, highlighting the importance of S474 residue in Kv3.1 channel trafficking and function in neurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Valdés-Albuernes2026,

title = {Computational modeling of ubiquitin specific protease 7 (USP7) complexes with N-benzylpiperidinol derivatives incorporating binding site flexibility},

author = {Jorge Luis Valdés-Albuernes and Erbio Díaz-Pico and José Luis Velázquez-Libera and Julio Caballero },

doi = {10.1016/j.jmgm.2025.109272},

year  = {2026},

date = {2026-01-08},

abstract = {Ubiquitin-specific protease 7 (USP7) is a key regulator of protein homeostasis, playing critical roles in various cellular processes, including DNA damage response, immune signaling, and oncogenesis. Targeting USP7 with small-molecule inhibitors has emerged as a promising therapeutic strategy, particularly in the context of cancer and autoimmune diseases. Among the diverse scaffolds explored for USP7 inhibition, N-benzylpiperidinol (NBP) derivatives have shown notable potential due to their structural versatility and bioactivity. Computationally, it is possible to access models of complexes between these inhibitors and USP7 by utilizing the crystallographic structures of USP7 available in the Protein Data Bank. In a classical approach, models of NBPs can be obtained within a rigid USP7 structure. In this work, we report models of complexes between 58 NBPs and variable conformations of USP7 using a flexible docking protocol employing the novel CorrEA method. As part of this protocol, we obtained diverse USP7 structures through molecular dynamics (MD) and selected complex models with inhibitors based on their biological activities. Model quality was validated using LigRMSD and interaction fingerprints (IFP). The flexible treatment of USP7 enabled the capture of binding-site conformational changes. These changes are critical for explaining the activity differences among the studied compounds.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Hernández-Rojas2026,

title = {Changes in transposable elements expression in male and female mice liver throughout aging},

author = {Bairon Hernández-Rojas and Paola Murgas and Gonzalo Riadi},

doi = {10.1007/s11357-025-02065-y},

year  = {2026},

date = {2026-01-06},

urldate = {2026-01-06},

abstract = {Aging has traditionally been studied through the lens of protein-coding genes, with a strong bias toward data derived from male organisms. As a result, the role of non-coding elements and potential sex-specific differences remains largely unexplored. Transposable elements (TEs), mobile sequences capable of altering genome structure and regulating gene expression, have recently gained attention for their roles in development and aging. However, despite this growing interest, key aspects of TE expression dynamics are still poorly characterized, particularly in female tissues. To address this gap, we analyzed TE expression in RNA-Seq liver tissue from male (8, 26, 60, 78, and 104 weeks) and female (3, 24, 48, and 72 weeks) mice. Our results reveal distinct TE expression trends between sexes. While previous studies report increased TE expression with aging, we identified a subset of TEs with decreasing expression over time, differing between males and females. We also observed inverse expression trends between a few TEs and their nearby genes, supporting a potential regulatory relationship. We identified TEs with changing expression (CE TEs) through age associated with nearby genes showing strong expression correlations (|ρ|≥ 0.6). In males, correlated genes such as Txnrd2, Mthfd1, and Dkk3 are involved in redox regulation, one-carbon metabolism, and Wnt signaling, respectively, while in females, Thrb and Cd55 are linked to metabolic regulation and immune protection. These associations suggest that TE activity may be functionally coupled to transcriptional programs relevant to liver physiology and aging. These findings highlight the importance of examining TE expression in both sexes and suggest their potential regulatory roles in age-related liver physiology.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Exploring a peripheral PIP2-binding site and its role in the alternative regulation of the TRP channel superfamily},

author = {L. Gonzalo Espinoza-Arcos and Mariela González-Avendaño and Matias Zuñiga-Bustos and Ricardo A. Zamora and Ariela Vergara-Jaque and Horacio Poblete},

doi = {10.1085/jgp.202413574},

year  = {2025},

date = {2025-11-03},

abstract = {Phosphatidylinositol 4,5-bisphosphate (PIP2) is recognized as an essential modulator of transient receptor potential (TRP) channels. Specifically, it influences the vanilloid receptor I (TRPV1), a pain receptor activated by a wide range of stimuli, including the binding of phospholipids, such as PIP2. The primary PIP2-binding site in TRPV1 has been identified through advanced techniques, revealing that the PIP2 binds to a specific pocket composed of positively charged residues located predominantly within the proximal C-terminus region. Additionally, a conserved segment with positively charged amino acids, K431 and R432, situated at the beginning of TRPV1's S1 transmembrane domain, has attracted considerable attention from the TRP research community. To date, our knowledge of this site's function and the subsequent effects following PIP2 binding is still emerging. In this work, MD simulations were conducted using coarse-grained models to investigate the binding dynamics of PIP2 on both WT and various mutated forms of TRPV1 channels. Our findings indicate that the K431A and R432A mutations significantly reduce the frequency of PIP2 contacts, suggesting that these mutated residues are part of a "peripheral binding pocket." This pocket seems to play a crucial role in facilitating the entry of PIP2 to the TRPV1 channel's primary binding site. Furthermore, our research has shown that these highly conserved residues within the TRPV subfamily are also structurally conserved across other TRP subfamilies, such as TRPM and TRPC, a detail not evident from sequence alignment alone. Consequently, we propose the existence of a structurally conserved peripheral PIP2-binding site shared among the diverse members of the TRP family, which can be categorized into distinct subfamilies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Unraveling Lewis base substitution in ansa-type frustrated Lewis pairs: how N → P replacement redefines adduct stability and H2 activation},

author = {César Barrales-Martínez and Javier Rosales-Rojas and Julio Caballero and Rocío Durán },

doi = {10.1039/d5ra06998j },

year  = {2025},

date = {2025-10-21},

urldate = {2025-10-21},

abstract = {This study investigates, through quantum-chemical calculations, how replacing nitrogen with phosphorus in ansa-type frustrated Lewis pairs reshapes both the FLP–CLA equilibrium and H2 activation thermodynamics. Energy decomposition analysis shows that the stabilization of ansa-phosphinoborane adducts arises mainly from steric relief, which compensates for weaker donor–acceptor interactions. For H2 activation, the energetic effect of Lewis base substitution reaches up to 35.9 kcal mol−1 and correlates directly with the proton affinity differences between the corresponding amines and phosphines. This correlation identifies proton affinity as a predictive descriptor of reactivity. By establishing how N → P substitution redefines the steric–electronic balance controlling adduct stability and H2 cleavage, this work provides conceptual design principles for tailoring frustrated Lewis pairs. These insights advance the molecular-level understanding of main-group systems and support the rational development of next-generation metal-free hydrogenation catalysts under sustainable conditions.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Navarro-Quezada2025,

title = {Charybdotoxin binding to Shaker K+ channels is temperature sensitive in high external K+ but not in high external Na+},

author = {Nieves Navarro-Quezada and Francisca Salas-Sepúlveda and Horacio Poblete and David Naranjo},

doi = {10.1085/jgp.202413590},

year  = {2025},

date = {2025-08-07},

urldate = {2025-08-07},

abstract = {Charybdotoxin (CTX), a peptide neurotoxin derived from the scorpion Leiurus quinquestriatus, binds to the external entrance of open voltage-gated K+ channels (VGKCs) with minimal conformational impact. By occluding the VGKC pore, CTX blocks passive K+ flow—a defining function of these membrane proteins. Due to its mechanistic simplicity and high signal-to-noise ratio, the CTX–VGKC interaction is an ideal system to investigate the molecular details of binding and unbinding. CTX bound to the Shaker VGKC exhibits thermal motion (wobbling) that permits access of external K+ to the channel pore. To test whether this wobbling is part of the reaction pathway during toxin–channel interaction, the energetic role of external K+ was examined in the association and dissociation kinetics. A high-affinity Shaker K427E-VGKC variant was expressed in Xenopus oocytes, and its activity was monitored via two-electrode voltage clamp between ∼10 and ∼30°C. Nanomolar applications of CTX to open and closed channels, in the presence of high external Na+ or high K+ concentrations, were used to measure blockade kinetics at different voltages and temperatures. In high K+, both the dissociation and association rates showed higher activation enthalpies, by ∼15 kJ/mol and ∼25 kJ/mol, respectively, compared with high Na+ conditions. However, the association rates under high Na+ and K+ were equal at ∼20°C, indicating a compensatory K+-induced activation entropy. We propose transient CTX-wobbling intermediates in both directions of the reaction pathway. Such a wobbling intermediate could enhance the diversity of productive collisions during association, increasing the efficacy of the scorpion venom.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Structural basis of the inhibition of TRPV1 by analgesic sesquiterpenes},

author = {Mariela González-Avendaño and Raul Sanchez-Hernandez and Miguel Benítez-Angeles and Irina A. Talyzina and Itzel Llorente and Felix Sierra and Angelica Mendez-Resendiz and Francisco Mercado and Ariela Vergara-Jaque and Alexander I. Sobolevsky and León D. Islas and Tamara Rosenbaum},

doi = {10.1073/pnas.2506560122},

year  = {2025},

date = {2025-07-25},

urldate = {2025-07-25},

abstract = {The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in primary nociceptive afferents, which participate in processes such as pain and inflammation. Considerable efforts have been directed toward finding inhibitors of TRPV1 and understanding the molecular details of their interactions with this channel. α-humulene (AH) is a sesquiterpene derived from plants such as hops and other members of Cannabaceae family, with a long history of popular use as an analgesic and anti-inflammatory. Using a combination of behavioral assays, electrophysiology, site-directed mutagenesis, cryo-EM, and molecular dynamics simulations, we show that AH inhibits TRPV1-related pain responses and currents by interacting with a region composed of the S2, S2-S3 linker, and S3 transmembrane segments and stabilizing the closed conformation of the channel. The interaction of ligands in this region of the TRPV1 channel has not been previously described and the results of the present study highlight that it may constitute part of a negative regulatory region. These findings allow us to understand the molecular basis by which substances such as some sesquiterpenes, abundantly found in medicinal plants used by humans for hundreds of years, reduce pain. Pain management can include the use of opioids, which results in hepatic and renal damage and possible addiction. Our study offers insight into a poorly understood group of compounds that could be used as scaffold to produce novel nonopioid analgesic therapies and clarifies the molecular mechanisms that underlie the effects of these analgesic molecules.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Loss of stimulator of interferon genes (STING) promotes accumulation of cholesterol and triglycerides throughout life in mice},

author = {Ian Riquelme and Daniela Carrillanca and Camila Sánchez-Pérez and Andrea Monterroza and Bairon Hernández-Rojas and Gonzalo Riadi and Gonzalo I Cancino and Paola Murgas},

doi = {10.1186/s40659-025-00624-3},

year  = {2025},

date = {2025-07-02},

urldate = {2025-07-02},

abstract = {The Stimulator of Interferon Genes (STING) pathway is pivotal in innate immunity, facilitating the detection of cytosolic DNA and initiating type I interferon-dependent responses. In addition to its immunological roles, STING has been increasingly associated with metabolic regulation, since research indicates that its inhibition can diminish inflammation, lipid accumulation, and tissue damage in obesity and other metabolic disorders. The findings have prompted the suggestion of STING inhibition as a viable treatment approach for metabolic illness. Nonetheless, the physiological function of STING in lipid homeostasis under normal settings remains largely unexplored, as does the impact of its absence on metabolism throughout various life stages in the absence of disease. This information deficit is crucial, particularly in light of the increasing interest in the long-term pharmacological suppression of STING.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}