Journals Current Opinion in Structural ...

Current Opinion in Structural Biology
Calvin P Lin, Elizabeth A Komives
The cellular process by which the protein ubiquitin (Ub) is covalently attached to a protein substrate involves Ub activating (E1s) and conjugating enzymes (E2s) that work together with a large variety of E3 ligases that impart substrate specificity. The largest family of E3s is the Cullin-RING ligase (CRL) family which utilizes a wide variety of substrate receptors, adapter proteins, and cooperating ligases. Cryo-electron microscopy (cryoEM) has revealed a wide variety of structures which suggest how Ub transfer occurs...
July 15, 2024: Current Opinion in Structural Biology
Mariela González-Avendaño, Joaquín López, Ariela Vergara-Jaque, Oscar Cerda
Adopting computational tools for analyzing extensive biological datasets has profoundly transformed our understanding and interpretation of biological phenomena. Innovative platforms have emerged, providing automated analysis to unravel essential insights about proteins and the complexities of their interactions. These computational advancements align with traditional studies, which employ experimental techniques to discern and quantify physical and functional protein-protein interactions (PPIs). Among these techniques, tandem mass spectrometry is notably recognized for its precision and sensitivity in identifying PPIs...
July 13, 2024: Current Opinion in Structural Biology
Souparna Chakrabarty, Shujuan Wang, Tanaya Roychowdhury, Stephen D Ginsberg, Gabriela Chiosis
Protein-protein interactions (PPIs) play a crucial role in cellular function and disease manifestation, with dysfunctions in PPI networks providing a direct link between stressors and phenotype. The dysfunctional Protein-Protein Interactome (dfPPI) platform, formerly known as epichaperomics, is a newly developed chemoproteomic method aimed at detecting dynamic changes at the systems level in PPI networks under stressor-induced cellular perturbations within disease states. This review provides an overview of dfPPIs, emphasizing the novel methodology, data analytics, and applications in disease research...
July 13, 2024: Current Opinion in Structural Biology
Joshua Hutchings, Elizabeth Villa
The combination of cryo-electron tomography and subtomogram analysis affords 3D high-resolution views of biological macromolecules in their native cellular environment, or in situ. Streamlined methods for acquiring and processing these data are advancing attainable resolutions into the realm of drug discovery. Yet regardless of resolution, structure prediction driven by artificial intelligence (AI) combined with subtomogram analysis is becoming powerful in understanding macromolecular assemblies. Automated and AI-assisted data mining is increasingly necessary to cope with the growing wealth of tomography data and to maximize the information obtained from them...
July 11, 2024: Current Opinion in Structural Biology
Raghuveera Kumar Goel, Nazmin Bithi, Andrew Emili
Co-fractionation mass spectrometry (CF-MS) uses biochemical fractionation to isolate and characterize macromolecular complexes from cellular lysates without the need for affinity tagging or capture. In recent years, this has emerged as a powerful technique for elucidating global protein-protein interaction networks in a wide variety of biospecimens. This review highlights the latest advancements in CF-MS experimental workflows including machine learning-guided analyses, for uncovering dynamic and high-resolution protein interaction landscapes with enhanced sensitivity, accuracy and throughput, enabling better biophysical characterization of endogenous protein complexes...
July 11, 2024: Current Opinion in Structural Biology
Nicoleta Siminea, Eugen Czeizler, Victor-Bogdan Popescu, Ion Petre, Andrei Păun
Network biology is a powerful framework for studying the structure, function, and dynamics of biological systems, offering insights into the balance between health and disease states. The field is seeing rapid progress in all of its aspects: data availability, network synthesis, network analytics, and impactful applications in medicine and drug development. We review the most recent and significant results in network biomedicine, with a focus on the latest data, analytics, software resources, and applications in medicine...
July 10, 2024: Current Opinion in Structural Biology
Manuel Carminati, Luca Vecchia, Lisa Stoos, Nicolas H Thomä
Pioneering transcription factors (TFs) can drive cell fate changes by binding their DNA motifs in a repressive chromatin environment. Recent structures illustrate emerging rules for nucleosome engagement: TFs distort the nucleosomal DNA to gain access or employ alternative DNA-binding modes with smaller footprints, they preferentially access solvent-exposed motifs near the entry/exit sites, and frequently interact with histones. The extent of TF-histone interactions, in turn, depends on the motif location on the nucleosome, the type of DNA-binding fold, and adjacent domains present...
July 10, 2024: Current Opinion in Structural Biology
Qiongdan Zhang, Wai Hei Lam, Yuanliang Zhai
To initiate DNA replication, it is essential to properly assemble a pair of replicative helicases at each replication origin. While the general principle of this process applies universally from prokaryotes to eukaryotes, the specific mechanisms governing origin selection, helicase loading, and subsequent helicase activation vary significantly across different species. Recent advancements in cryo-electron microscopy (cryo-EM) have revolutionized our ability to visualize large protein or protein-DNA complexes involved in the initiation of DNA replication...
July 9, 2024: Current Opinion in Structural Biology
Attila Csikász-Nagy, Erzsébet Fichó, Santiago Noto, István Reguly
Interactions between thousands of proteins define cells' protein-protein interaction (PPI) network. Some of these interactions lead to the formation of protein complexes. It is challenging to identify a protein complex in a haystack of protein-protein interactions, and it is even more difficult to predict all protein complexes of the complexome. Simulations and machine learning approaches try to crack these problems by looking at the PPI network or predicted protein structures. Clustering of PPI networks led to the first protein complex predictions, while most recently, atomistic models of protein complexes and deep-learning-based structure prediction methods have also emerged...
July 9, 2024: Current Opinion in Structural Biology
Sanjay Ramprasad, Afua Nyarko
Many critical biological processes depend on protein complexes that exist as ensembles of subcomplexes rather than a discrete complex. The subcomplexes dynamically interconvert with one another, and the ability to accurately resolve the composition of the diverse molecular species in the ensemble is crucial for understanding the contribution of each subcomplex to the overall function of the protein complex. Advances in computational programs have made it possible to predict the various molecular species in these ensembles, but experimental approaches to identify the pool of subcomplexes and associated stoichiometries are often challenging...
July 8, 2024: Current Opinion in Structural Biology
Peter H Whitney, Timothée Lionnet
Cell states result from the ordered activation of gene expression by transcription factors. Transcription factors face opposing design constraints: they need to be dynamic to trigger rapid cell state transitions, but also stable enough to maintain terminal cell identities indefinitely. Recent progress in live-cell single-molecule microscopy has helped define the biophysical principles underlying this paradox. Beyond transcription factor activity, single-molecule experiments have revealed that at nearly every level of transcription regulation, control emerges from multiple short-lived stochastic interactions, rather than deterministic, stable interactions typical of other biochemical pathways...
July 1, 2024: Current Opinion in Structural Biology
Chase M Hutchins, Alemayehu A Gorfe
The intrinsically disordered, lipid-modified membrane anchor of small GTPases is emerging as a critical modulator of function through its ability to sort lipids in a conformation-dependent manner. We reviewed recent computational and experimental studies that have begun to shed light on the sequence-ensemble-function relationship in this unique class of lipidated intrinsically disordered regions (LIDRs).
June 28, 2024: Current Opinion in Structural Biology
Luke Botticelli, Anna A Bakhtina, Nathan K Kaiser, Andrew Keller, Seth McNutt, James E Bruce, Feixia Chu
Structural information on protein-protein interactions (PPIs) is essential for improved understanding of regulatory interactome networks that confer various physiological and pathological responses. Additionally, maladaptive PPIs constitute desirable therapeutic targets due to inherently high disease state specificity. Recent advances in chemical cross-linking strategies coupled with mass spectrometry (XL-MS) have positioned XL-MS as a promising technology to not only elucidate the molecular architecture of individual protein assemblies, but also to characterize proteome-wide PPI networks...
June 26, 2024: Current Opinion in Structural Biology
Syeda Rehana Zia, Adriana Coricello, Giovanni Bottegoni
By incorporating full flexibility and enabling the quantification of crucial parameters such as binding free energies and residence times, methods for investigating protein-ligand binding and unbinding via molecular dynamics provide details on the involved mechanisms at the molecular level. While these advancements hold promise for impacting drug discovery, a notable drawback persists: their relatively time-consuming nature limits throughput. Herein, we survey recent implementations which, employing a blend of enhanced sampling techniques, a clever choice of collective variables, and often machine learning, strive to enhance the efficiency of new and previously reported methods without compromising accuracy...
June 25, 2024: Current Opinion in Structural Biology
Tiziana Ginex, Javier Vázquez, Carolina Estarellas, F Javier Luque
The expansion of the chemical space to tangible libraries containing billions of synthesizable molecules opens exciting opportunities for drug discovery, but also challenges the power of computer-aided drug design to prioritize the best candidates. This directly hits quantum mechanics (QM) methods, which provide chemically accurate properties, but subject to small-sized systems. Preserving accuracy while optimizing the computational cost is at the heart of many efforts to develop high-quality, efficient QM-based strategies, reflected in refined algorithms and computational approaches...
June 23, 2024: Current Opinion in Structural Biology
Shuo Han, Ling-Ling Chen
The nucleolus functions as a multi-layered regulatory hub for ribosomal RNA (rRNA) biogenesis and ribosome assembly. Long noncoding RNAs (lncRNAs) in the nucleolus, originated from transcription by different RNA polymerases, have emerged as critical players in not only fine-tuning rRNA transcription and processing, but also shaping the organization of the multi-phase nucleolar condensate. Here, we review the diverse molecular mechanisms by which functional lncRNAs operate in the nucleolus, as well as their profound implications in a variety of biological processes...
June 22, 2024: Current Opinion in Structural Biology
Sarah Nemsick, Anders S Hansen
Approximately 11% of human genes are transcribed by a bidirectional promoter (BDP), defined as two genes with <1 kb between their transcription start sites. Despite their evolutionary conservation and enrichment for housekeeping genes and oncogenes, the regulatory role of BDPs remains unclear. BDPs have been suggested to facilitate gene coregulation and/or decrease expression noise. This review discusses these potential regulatory functions through the context of six prospective underlying mechanistic models: a single nucleosome free region, shared transcription factor/regulator binding, cooperative negative supercoiling, bimodal histone marks, joint activation by enhancer(s), and RNA-mediated recruitment of regulators...
June 20, 2024: Current Opinion in Structural Biology
Alex J Noble, Alex de Marco
Cryogenic-focused ion beam (cryo-FIB) instruments became essential for high-resolution imaging in cryo-preserved cells and tissues. Cryo-FIBs use accelerated ions to thin samples that would otherwise be too thick for cryo-electron microscopy (cryo-EM). This allows visualizing cellular ultrastructures in near-native frozen hydrated states. This review describes the current state-of-the-art capabilities of cryo-FIB technology and its applications in structural cell and tissue biology. We discuss recent advances in instrumentation, imaging modalities, automation, sample preparation protocols, and targeting techniques...
June 19, 2024: Current Opinion in Structural Biology
Abigail J I Watson, Alberto Bartesaghi
Cryogenic electron tomography (cryo-ET), a method that enables the viewing of biomolecules in near-native environments at high resolution, is rising in accessibility and applicability. Over the past several years, once slow sample preparation and data collection procedures have seen innovations which enable rapid collection of the large datasets required for attaining high resolution structures. Increased data availability has provided a driving force for exciting improvements in cryo-ET data processing methodologies throughout the entire processing pipeline and the development of accessible graphical user interfaces (GUIs) that enable individuals inexperienced in computational fields to convert raw tilt series into 3D structures...
June 17, 2024: Current Opinion in Structural Biology
Rebecca K Stephens, Yekaterina A Miroshnikova
Cell fate changes require rewiring of transcriptional programs to generate functionally specialized cell states. Reconfiguration of transcriptional networks requires overcoming epigenetic barriers imposed by silenced heterochromatin in order to activate lineage-specific genes. Further, cell fate decisions are made in a tissue-specific context, where cells are physically linked to each other as well as to the connective tissue environment. Here, cells are continuously exposed to a multitude of mechanical forces emanating from cellular dynamics in their local microenvironments, for example through cell movements, cell divisions, tissue contractions, or fluid flow...
June 17, 2024: Current Opinion in Structural Biology
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