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The structural and functional dynamics of BiP and Grp94: opportunities for therapeutic discovery

Trends in Pharmacological Sciences 2025年第5期46卷 453-467页

作者： Obaseki, Ikponwmosa Ndolo, Chioma C. Adedeji, Ayodeji A. Popoola, Hannah O. Kravats, Andrea N. Department of Chemistry & Biochemistry Miami University Oxford 45056 OH United States Cell Molecular and Structural Biology Graduate Program Miami University Oxford 45056 OH United States

Binding immunoglobulin protein (BiP) and glucose-regulated protein 94 (Grp94) are endoplasmic reticulum (ER)-localized molecular chaperones that ensure proper protein folding and maintain protein homeostasis. However, overexpression of these chaperones during ER stress can contribute to disease progression in numerous pathologies. Although these chaperones represent promising therapeutic targets, their inhibition has been challenged by gaps in understanding of targetable chaperone features and their complex biology. To overcome these challenges, a new assay has been developed to selectively target BiP, and compounds that exploit subtle conformational changes of Grp94 have been designed. This review summarizes recent advances in elucidating structural and functional dynamics of BiP and Grp94. We explore leveraging this information to develop novel therapeutic interventions. Finally, given the recent advances in computing, we discuss how machine learning methods can be used to accelerate drug discovery efforts. © 2025 Elsevier Ltd

关键词： BiP drug design endoplasmic reticulum stress Grp94 molecular chaperones

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MUC1 and MUC4 expression are inversely correlated and trigger immunological response and transport pathways in adult-type diffuse gliomas

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Computers in biology and Medicine 2025年 187卷 109730-109730页

作者： Machado, Gabriel Cardoso Ferrer, Valéria Pereira Graduate Program in Pathological Anatomy Faculty of Medicine Rio de Janeiro Federal University Rio de Janeiro Brazil Laboratory of Cell and Molecular Biology of Tumors Department of Cell and Molecular Biology Biology Institute Fluminense Federal University Niterói Rio de Janeiro Brazil

Adult-type diffuse gliomas arise from glial or progenitor cells. These tumors are currently classified as astrocytoma isocitrate dehydrogenase (IDH)-mutant or IDH-mutant oligodendroglioma with co-deletion of chromosomal arms 1p and 19q, both of which could be either slow-growing tumors, or glioblastoma (GBM), which is a more aggressive tumor. Despite advances in diagnosis and treatment, the median survival time after GBM diagnosis remains low at approximately 15 months, with a 5-year overall survival (OS) rate of 6.8 %. Therefore, new biomarker and therapeutic target discoveries are required to improve prognosis. Mucin 1 (MUC1) and MUC4 are membrane-bound mucins and potential biomarkers of several tumors. However, the role of these mucins in adult gliomas has not been well explored. In this retrospective study, in silico analysis of data from patients with adult-type diffuse glioma revealed differential methylation and expression patterns of MUC1 and MUC4 between GBM and non-GBM groups. In the GBM group, decreased methylation and elevated expression of MUC1 were observed (r = −0.25, p © 2025 Elsevier Ltd

关键词： Methylation

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The filopodial myosin DdMyo7 is a slow, calcium-regulated motor

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Journal of Biological Chemistry 2025年第5期301卷 108371页

作者： Eddington, Casey Titus, Margaret A. Department of Genetics Cell Biology and Development University of Minnesota MinneapolisMN United States Graduate Program in Biochemistry Molecular Biology and Biophysics University of Minnesota MinneapolisMN United States

MyTH4-FERM (MF) myosins are a family of molecular motors with critical roles in the formation and organization of thin membrane protrusions supported by parallel bundles of actin - filopodia, microvilli, and stereocilia. The amoeboid MF myosin DdMyo7 is essential for filopodia formation but its mechanism of action is unknown. The motor properties of a forced-dimer of the DdMyo7 motor were characterized using an in vitro motility assay to address this question. The DdMyo7 motor associates with two different light chains, the Dictyostelium calmodulins CalA and CalB, whose binding is shown to be sensitive to the presence of calcium. Total internal reflection fluorescence motility assays of the dimerized DdMyo7 motor reveal that it is a slow, processive motor that moves along actin at ∼ 40 nm/sec, and the activity of the motor is significantly reduced in the presence of Ca2+. The speed of DdMyo7 is similar to that of other Myo7 family members such as human Myo7A and fly DmMyo7A, but is at least 10-fold slower than the mammalian filopodial MF myosin, Myo10. The results show that evolutionarily distant native filopodial myosins can promote filopodia elongation using motors with distinct properties, revealing diverse mechanisms of myosin-based filopodia formation. © 2025 The Authors

关键词： Mammals

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The pentameric chloride channel BEST1 is activated by extracellular GABA

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Proceedings of the National Academy of Sciences of the United States of America 2025年第16期122卷 e2424474122页

作者： Pant, Swati Tam, Stephanie W. Long, Stephen B. Structural Biology Program Memorial Sloan Kettering Cancer Center New York 10065 NY United States Graduate Program in Biochemistry and Structural Biology Cell and Developmental Biology and Molecular Biology Weill Cornell Medicine Graduate School of Medical Sciences New York 10065 NY United States Graduate Program in Physiology Biophysics and Systems Biology Weill Cornell Medicine Graduate School of Medical Sciences New York 10065 NY United States

Bestrophin-1 (BEST1) is a chloride channel expressed in the eye and other tissues of the body. A link between BEST1 and the principal inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been proposed. The most appreciated receptors for extracellular GABA are the GABA_B G-protein-coupled receptors and the pentameric GABA_A chloride channels, both of which have fundamental roles in the central nervous system. Here, we demonstrate that BEST1 is directly activated by GABA. Through functional studies and atomic-resolution structures of human and chicken BEST1, we identify a GABA binding site on the channel’s extracellular side and determine the mechanism by which GABA binding stabilizes opening of the channel’s central gate. This same gate, “the neck,” is activated by intracellular [Ca²⁺], indicating that BEST1 is controlled by ligands from both sides of the membrane. The studies demonstrate that BEST1, which shares no structural homology with GABA_A receptors, is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied. © 2025 the Author(s).

关键词： activation bestrophin chloride channel GABA receptor

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Invasion and metastasis in cancer:molecular insights and therapeutic targets

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Signal Transduction and Targeted Therapy 2025年第3期10卷 1503-1540页

作者： Yongxing Li Fengshuo Liu Qingjin Cai Lijun Deng Qin Ouyang Xiang H.-F.Zhang Ji Zheng Department of Urology Urologic Surgery CenterXinqiao HospitalThird Military Medical University(Army Medical University)ChongqingChina State Key Laboratory of Trauma and Chemical Poisoning Third Military Medical University(Army Medical University)ChongqingChina Lester and Sue Smith Breast Center Baylor College of MedicineHoustonTXUSA Dan L.Duncan Cancer Center Baylor College of MedicineHoustonTXUSA Department of Molecular and Cellular Biology Baylor College of MedicineHoustonTXUSA McNair Medical Institute Baylor College of MedicineHoustonTXUSA Graduate School of Biomedical Science Cancer and Cell Biology ProgramBaylor College of MedicineHoustonTXUSA Department of Medicinal Chemistry Third Military Medical University(Army Medical University)ChongqingChina

The progression of malignant tumors leads to the development of secondary tumors in various organs,including bones,the brain,liver,and *** metastatic process severely impacts the prognosis of patients,significantly affecting their quality of life and survival *** efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management ***,a comprehensive understanding of the biological foundations of tumor metastasis,identification of pivotal signaling pathways,and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic ***,current research is primarily focused on metastasis within specific cancer types,leaving significant gaps in our understanding of the complex metastatic cascade,organ-specific tropism mechanisms,and the development of targeted *** this study,we examine the sequential processes of tumor metastasis,elucidate the underlying mechanisms driving organ-tropic metastasis,and systematically analyze therapeutic strategies for metastatic tumors,including those tailored to specific organ ***,we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone *** objective is to offer insights that can inform future research and clinical practice in this crucial field.

关键词： secondary tumors invasion metastatic process therapeutic targets molecular insights malignant tumors tumor metastasis metastasis

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Advances in AAV capsid engineering: Integrating rational design, directed evolution and machine learning

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molecular Therapy 2025年第5期33卷 1937-1945页

作者： Nisanov, Alan M. Rivera de Jesús, Julio A. Schaffer, David V. Department of Chemistry University of California Berkeley Berkeley 94720 CA United States Department of Chemical and Biomolecular Engineering University of California Berkeley Berkeley 94720 CA United States Department of Bioengineering University of California Berkeley Berkeley 94720 CA United States Graduate Program in Bioengineering University of California Berkeley San Francisco and University of California Berkeley 94720 CA United States Department of Neurological Surgery University of California San Francisco 94143 CA United States Department of Molecular and Cell Biology University of California Berkeley Berkeley 94720 CA United States

Adeno-associated virus (AAV) has emerged as a highly promising vector for human gene therapy due to its favorable safety profile, versatility, and ability to transduce a wide range of tissues. However, natural AAV serotypes have shortcomings, including suboptimal transduction efficiency, pre-existing immunity, and a lack of tissue specificity, that hinder their therapeutic potential. To address these challenges, significant efforts are being applied to engineer novel AAV capsids. Rational design leverages structural insights to enhance capsid properties, directed evolution enables unbiased selection of superior variants, and machine learning accelerates discovery by computational analysis of high-throughput screening results to enable predictive algorithms. These strategies have yielded novel capsids with improved transduction efficiency, reduced immunogenicity, and enhanced tissue targeting. Future advances that continue to integrate such multi-disciplinary approaches will further drive the clinical translation of AAV-based therapies. © 2025 The Authors

关键词： AAV directed evolution gene therapy high-throughput screening machine learning next generation sequencing NGS rational design

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Generative and predictive neural networks for the design of functional RNA molecules

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Nature Communications 2025年第1期16卷 1-17页

作者： Riley, Aidan T. Robson, James M. Ulanova, Aiganysh Green, Alexander A. Department of Biomedical Engineering Boston University Boston MA United States Biological Design Center Boston University Boston MA United States College of Arts and Sciences Biochemistry and Molecular Biology Program Boston University Boston MA United States Faculty of Computing and Data Sciences Boston University Boston MA United States Molecular Biology Cell Biology & Biochemistry Program Graduate School of Arts and Sciences Boston University Boston MA United States

RNA is a remarkably versatile molecule that has been engineered for applications in therapeutics, diagnostics, and in vivo information-processing systems. However, the complex relationship between the sequence, structure, and function of RNA often necessitates extensive experimental screening of candidate sequences. Here we present a generalized, efficient neural network architecture that utilizes the sequence and structure of RNA molecules (SANDSTORM) to inform functional predictions across a diverse range of settings. We pair these predictive models with generative adversarial RNA design networks (GARDN), allowing the generative modelling of a diverse range of functional RNA molecules with targeted experimental attributes. This approach enables the design of novel sequence candidates that outperform those encountered during training or returned by classical thermodynamic algorithms, and can be deployed using as few as 384 example sequences. SANDSTORM and GARDN thus represent powerful new predictive and generative tools for the development of RNA molecules with improved function. © The Author(s) 2025.

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Actin Filament Pointed Ends: Assays for Regulation of Assembly and Disassembly by Tropomodulin and Tropomyosin

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Cytoskeleton 2025年第0期 2025 Feb 24页

作者： Yamashiro, Sawako Shekhar, Shashank Novak, Stefanie M. Biswas, Sudipta Gregorio, Carol C. Fowler, Velia M. Laboratory of Single-Molecule Cell Biology Kyoto University Graduate School of Biostudies Kyoto Japan Departments of Physics Cell Biology and Biochemistry Emory University Atlanta GA United States Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program The University of Arizona Tucson AZ United States Department of Medicine Cardiovascular Research Institute Icahn School of Medicine New York NY United States Department of Biological Sciences University of Delaware Newark DE United States

Actin filaments are dynamic polymers whose length depends on regulated monomer association and dissociation at their ends. Actin barbed-end dynamics are relatively better understood, primarily due to the approximately tenfold faster subunit on/off rates at barbed versus pointed ends. We present experimental approaches to selectively assay actin pointed-end regulation using bulk biochemistry, single filament imaging, and live cell microscopy with an emphasis on tropomodulins (Tmods), a conserved family of eukaryotic proteins that specifically cap pointed ends. Average pointed-end assembly/disassembly rates are measured in bulk solution using pyrene-labeled actin and barbed end-capping protein CapZ. Direct rate measurements of individual pointed ends are performed via microfluidic-assisted total internal reflection fluorescence microscopy (mf-TIRF). Actin pointed-end dynamics in living cells are examined in striated muscle cells expressing fluorescent actin, where the regular arrays of 1- to 2-μm-long actin filaments in sarcomeres enable visualization of filament pointed and barbed ends. These assays will also help advance our understanding of other pointed end regulators, including cyclase-associated protein and leiomodins, which have been implicated in filament stabilization, disassembly, and elongation. This work is relevant to the musculoskeletal field, where precise regulation of filament lengths is particularly critical for sarcomere organization and striated muscle contraction. © 2025 The Author(s). Cytoskeleton published by Wiley Periodicals LLC.

关键词： actin polymerization leiomodin striated muscle sarcomeres tropomodulin tropomyosin

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Double-sided niche regulation in skin stem cell and cancer: mechanisms and clinical applications

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molecular Cancer 2025年第1期24卷 1-61页

作者： Pham, Trang Thao Quoc Kuo, Yung-Che Chang, Wei-Ling Weng, Hao-Jui Huang, Yen-Hua International Ph.D. Program in Cell Therapy and Regenerative Medicine College of Medicine Taipei Medical University Taipei Taiwan TMU Research Center for Cell Therapy and Regeneration Medicine Taipei Medical University Taipei Taiwan Department of Dermatology Taipei Medical University-Shuang Ho Hospital New Taipei City Taiwan Department of Dermatology School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Graduate Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei Taiwan Department of Biochemistry and Molecular Cell Biology School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Graduate Institute of Medical Sciences College of Medicine Taipei Medical University Taipei Taiwan

The niche microenvironment plays a crucial role in regulating the fate of normal skin stem cells (SSCs) and cancer stem cells (CSCs). Therapeutically targeting the CSC niche holds promise as an effective strategy; however, the dual effects of shared SSC niche signaling in CSCs have contributed to the aggressive characteristics of tumors and poor survival rates in skin cancer patients. The lack of a clear underlying mechanism has significantly hindered drug development for effective treatment. This article explores recent advances in understanding how niche factors regulate cell fate determination between skin stem cells and skin CSCs, along with their clinical implications. The dual roles of key components of the adhesive niche, including the dermo-epidermal junction and adherens junction, various cell types—especially immune cells and fibroblasts—as well as major signaling pathways such as Sonic hedgehog (Shh), Wingless-related integration site (Wnt)/β-catenin, YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif), and Notch, are highlighted. Additionally, recent advances in clinical trials and drug development targeting these pathways are discussed. Overall, this review provides valuable insights into the complex interactions between skin cancer stem cells and their microenvironment, laying the groundwork for future research and clinical strategies.

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Structure of the human TWIK-2 potassium channel and its inhibition by pimozide

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Proceedings of the National Academy of Sciences of the United States of America 2025年第19期122卷 e2425709122页

作者： Nandish K Khanra Chongyuan Wang Bryce D Delgado Stephen B Long Structural Biology Program Memorial Sloan Kettering Cancer Center New York NY 10065. Graduate Program in Biochemistry and Structural Biology Cell and Developmental Biology and Molecular Biology Weill Cornell Medicine Graduate School of Medical Sciences New York NY 10065.

The potassium channel TWIK-2 is crucial for ATP-induced activation of the NLRP3 inflammasome in macrophages. The channel is a member of the two-pore domain potassium (K2P) channel superfamily and an emerging therapeutic target to mitigate severe inflammatory injury involving NLRP3 activation. We report the cryo-EM structure of human TWIK-2. In comparison to other K2P channels, the structure reveals an unusual "up" conformation of Tyr111 in the selectivity filter and a resulting SF1-P1 pocket behind the filter. Density for acyl chains is present in fenestrations within the transmembrane region that connects the central cavity of the pore to the lipid membrane. Despite its importance as a drug target, limited pharmacological tools are available for TWIK-2. A previous study suggested that the FDA-approved small molecule pimozide might inhibit TWIK-2. Using a reconstituted system, we show that pimozide directly inhibits the channel and we determine a cryo-EM structure of a complex with the drug. Pimozide displaces the acyl chains within the fenestrations and binds below the selectivity filter where it would impede ion permeation. The drug may access its binding site by lateral diffusion in the membrane, suggesting that other hydrophobic small molecules could have utility for inhibiting TWIK-2. The work defines the structure of TWIK-2 and provides a structural foundation for development of more specific inhibitors with potential utility as anti-inflammatory drugs.

关键词： K2P channel K2P6 NLRP3 inflammasome potassium channel therapeutic

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