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Editorial overview: New concept in drug discovery 编辑综述：药物发现的新概念
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2024-08-20 DOI: 10.1016/j.sbi.2024.102911
Andrea Cavalli, Alessio Ciulli
{"title":"Editorial overview: New concept in drug discovery","authors":"Andrea Cavalli, Alessio Ciulli","doi":"10.1016/j.sbi.2024.102911","DOIUrl":"10.1016/j.sbi.2024.102911","url":null,"abstract":"","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102911"},"PeriodicalIF":6.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142011687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Supercomputing in the biological sciences: Toward Zettascale and Yottascale simulations 生物科学中的超级计算：迈向 Zettascale 和 Yottascale 模拟。
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2024-08-19 DOI: 10.1016/j.sbi.2024.102889
Karissa Sanbonmatsu
{"title":"Supercomputing in the biological sciences: Toward Zettascale and Yottascale simulations","authors":"Karissa Sanbonmatsu","doi":"10.1016/j.sbi.2024.102889","DOIUrl":"10.1016/j.sbi.2024.102889","url":null,"abstract":"<div><p>Molecular simulations of biological systems tend to be significantly more compute-intensive than those in materials science and astrophysics, due to important contributions of long-range electrostatic forces and large numbers of time steps (&gt;1E9) required. Simulations of biomolecular complexes of microseconds to milliseconds are considered state-of-the-art today. However, these time scales are miniscule in comparison to physiological time scales relevant to molecular machine activity, drug action, and elongation cycles for protein synthesis, RNA synthesis, and DNA synthesis (seconds to days). While an exascale supercomputer has simulated an entire virus for nanoseconds, this supercomputer would need to be 10 billion times faster to simulate that virus for 3 hours of physiological time, demonstrating the insatiable need for computing power. With growing interest in computational drug design from the pharmaceutical sector, the biological sciences are positioned to be an industry driver in computing.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102889"},"PeriodicalIF":6.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Probing protein–DNA interactions and compaction in nanochannels 探测纳米通道中蛋白质与 DNA 的相互作用和压实。
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2024-08-19 DOI: 10.1016/j.sbi.2024.102914
Robert Riehn
{"title":"Probing protein–DNA interactions and compaction in nanochannels","authors":"Robert Riehn","doi":"10.1016/j.sbi.2024.102914","DOIUrl":"10.1016/j.sbi.2024.102914","url":null,"abstract":"<div><p>DNA confined to nanofluidic channels with a cross-section from tens to hundreds of nm wide and hundreds of microns long stretches in an equilibrium process free of flow or end tethering. Because DNA is free to move along the channel axis, its extension is exquisitely sensitive to DNA–DNA interactions and the DNA persistence length, as well as the contour length. We discuss how this sensitivity has been used to probe DNA-protein interactions at physiological concentrations of both DNA and proteins.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102914"},"PeriodicalIF":6.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Transcription start site choice regulates HIV-1 RNA conformation and function 转录起始位点的选择调节 HIV-1 RNA 的构象和功能。
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2024-08-14 DOI: 10.1016/j.sbi.2024.102896
Karin Musier-Forsyth , Alan Rein , Wei-Shau Hu
{"title":"Transcription start site choice regulates HIV-1 RNA conformation and function","authors":"Karin Musier-Forsyth ,&nbsp;Alan Rein ,&nbsp;Wei-Shau Hu","doi":"10.1016/j.sbi.2024.102896","DOIUrl":"10.1016/j.sbi.2024.102896","url":null,"abstract":"<div><p>HIV-1, the causative agent of AIDS, is a retrovirus that packages two copies of unspliced viral RNA as a dimer into newly budding virions. The unspliced viral RNA also serves as an mRNA template for translation of two polyproteins. Recent studies suggest that the fate of the viral RNA (genome or mRNA) is determined at the level of transcription. RNA polymerase II uses heterogeneous transcription start sites to generate major transcripts that differ in only two guanosines at the 5ʹ end. Remarkably, this two-nucleotide difference is sufficient to alter the structure of the 5ʹ-untranslated region and generate two pools of RNA with distinct functions. The presence of both RNA species is needed for optimal viral replication and fitness.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102896"},"PeriodicalIF":6.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structural and biophysical dissection of RNA conformational ensembles RNA 构象组合的结构和生物物理剖析
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2024-08-14 DOI: 10.1016/j.sbi.2024.102908
Steve L. Bonilla , Alisha N. Jones , Danny Incarnato
{"title":"Structural and biophysical dissection of RNA conformational ensembles","authors":"Steve L. Bonilla ,&nbsp;Alisha N. Jones ,&nbsp;Danny Incarnato","doi":"10.1016/j.sbi.2024.102908","DOIUrl":"10.1016/j.sbi.2024.102908","url":null,"abstract":"<div><p>RNA's ability to form and interconvert between multiple secondary and tertiary structures is critical to its functional versatility and the traditional view of RNA structures as static entities has shifted towards understanding them as dynamic conformational ensembles. In this review we discuss RNA structural ensembles and their dynamics, highlighting the concept of conformational energy landscapes as a unifying framework for understanding RNA processes such as folding, misfolding, conformational changes, and complex formation. Ongoing advancements in cryo-electron microscopy and chemical probing techniques are significantly enhancing our ability to investigate multiple structures adopted by conformationally dynamic RNAs, while traditional methods such as nuclear magnetic resonance spectroscopy continue to play a crucial role in providing high-resolution, quantitative spatial and temporal information. We discuss how these methods, when used synergistically, can provide a comprehensive understanding of RNA conformational ensembles, offering new insights into their regulatory functions.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102908"},"PeriodicalIF":6.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0959440X24001350/pdfft?md5=bc1f80228c1ae22467485bb8f3608fdb&pid=1-s2.0-S0959440X24001350-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141985666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The role of intrinsic protein disorder in regulation of cyclin-dependent kinases 内在蛋白质紊乱在周期蛋白依赖性激酶调控中的作用
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2024-08-13 DOI: 10.1016/j.sbi.2024.102906
Aaron H. Phillips, Richard W. Kriwacki
{"title":"The role of intrinsic protein disorder in regulation of cyclin-dependent kinases","authors":"Aaron H. Phillips,&nbsp;Richard W. Kriwacki","doi":"10.1016/j.sbi.2024.102906","DOIUrl":"10.1016/j.sbi.2024.102906","url":null,"abstract":"<div><p>While the structure/function paradigm for folded domains was established decades ago, our understanding of how intrinsically disordered regions (IDRs) contribute to biological function is still evolving. IDRs exist as conformational ensembles that can range from highly compact to highly extended depending on their sequence composition. IDR sequences are less conserved than those of folded domains, but often display short, conserved segments termed short linear motifs (SLiMs), that often mediate protein–protein interactions and are often regulated by posttranslational modifications, giving rise to complex functionality when multiple, differently regulated SLiMs are combined. This combinatorial functionality was associated with signaling and regulation soon after IDRs were first recognized as functional elements within proteins. Here, we discuss roles for disorder in proteins that regulate cyclin-dependent kinases, the master timekeepers of the eukaryotic cell cycle. We illustrate the importance of intrinsic flexibility in the transmission of regulatory signals by these entirely disordered proteins.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102906"},"PeriodicalIF":6.1,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141979665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structure-based approaches in synthetic lethality strategies 基于结构的合成致死策略
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2024-08-12 DOI: 10.1016/j.sbi.2024.102895
Francesco Rinaldi , Stefania Girotto
{"title":"Structure-based approaches in synthetic lethality strategies","authors":"Francesco Rinaldi ,&nbsp;Stefania Girotto","doi":"10.1016/j.sbi.2024.102895","DOIUrl":"10.1016/j.sbi.2024.102895","url":null,"abstract":"<div><p>Evolution has fostered robust DNA damage response (DDR) mechanisms to combat DNA lesions. However, disruptions in this intricate machinery can render cells overly reliant on the remaining functional but often less accurate DNA repair pathways. This increased dependence on error-prone pathways may result in improper repair and the accumulation of mutations, fostering genomic instability and facilitating the uncontrolled cell proliferation characteristic of cancer initiation and progression. Strategies based on the concept of synthetic lethality (SL) leverage the inherent genomic instability of cancer cells by targeting alternative pathways, thereby inducing selective death of cancer cells. This review emphasizes recent advancements in structural investigations of pivotal SL targets. The significant contribution of structure-based methodologies to SL research underscores their potential impact in characterizing the growing number of SL targets, largely due to advances in next-generation sequencing. Harnessing these approaches is essential for advancing the development of precise and personalized SL therapeutic strategies.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102895"},"PeriodicalIF":6.1,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0959440X24001222/pdfft?md5=c8115c810565f45aed7da20325db8917&pid=1-s2.0-S0959440X24001222-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141964629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Challenges, advances, and opportunities in RNA structural biology by Cryo-EM 利用低温电子显微镜研究 RNA 结构生物学的挑战、进展和机遇。
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2024-08-08 DOI: 10.1016/j.sbi.2024.102894
Steve L. Bonilla, Karen Jang
{"title":"Challenges, advances, and opportunities in RNA structural biology by Cryo-EM","authors":"Steve L. Bonilla,&nbsp;Karen Jang","doi":"10.1016/j.sbi.2024.102894","DOIUrl":"10.1016/j.sbi.2024.102894","url":null,"abstract":"<div><p>RNAs are remarkably versatile molecules that can fold into intricate three-dimensional (3D) structures to perform diverse cellular and viral functions. Despite their biological importance, relatively few RNA 3D structures have been solved, and our understanding of RNA structure–function relationships remains in its infancy. This limitation partly arises from challenges posed by RNA's complex conformational landscape, characterized by structural flexibility, formation of multiple states, and a propensity to misfold. Recently, cryo-electron microscopy (cryo-EM) has emerged as a powerful tool for the visualization of conformationally dynamic RNA-only 3D structures. However, RNA's characteristics continue to pose challenges. We discuss experimental methods developed to overcome these hurdles, including the engineering of modular modifications that facilitate the visualization of small RNAs, improve particle alignment, and validate structural models.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102894"},"PeriodicalIF":6.1,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0959440X24001210/pdfft?md5=e1a7014f5342ee0d13f08281bd88235b&pid=1-s2.0-S0959440X24001210-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structures and compositional dynamics of Mediator in transcription regulation 转录调控中 Mediator 的结构和组成动态。
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2024-07-26 DOI: 10.1016/j.sbi.2024.102892
Tao Li, Ti-Chun Chao, Kuang-Lei Tsai
{"title":"Structures and compositional dynamics of Mediator in transcription regulation","authors":"Tao Li,&nbsp;Ti-Chun Chao,&nbsp;Kuang-Lei Tsai","doi":"10.1016/j.sbi.2024.102892","DOIUrl":"10.1016/j.sbi.2024.102892","url":null,"abstract":"<div><p>The eukaryotic Mediator, comprising a large Core (cMED) and a dissociable CDK8 kinase module (CKM), functions as a critical coregulator during RNA polymerase II (RNAPII) transcription. cMED recruits RNAPII and facilitates the assembly of the pre-initiation complex (PIC) at promoters. In contrast, CKM prevents RNAPII binding to cMED while simultaneously exerting positive or negative influence on gene transcription through its kinase function. Recent structural studies on cMED and CKM have revealed their intricate architectures and subunit interactions. Here, we explore these structures, providing a comprehensive insight into Mediator (cMED-CKM) architecture and its potential mechanism in regulating RNAPII transcription. Additionally, we discuss the remaining puzzles that require further investigation to fully understand how cMED coordinates with CKM to regulate transcription in various events.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102892"},"PeriodicalIF":6.1,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0959440X24001192/pdfft?md5=10fec5f8a1c983ec13ee4b17d387ccba&pid=1-s2.0-S0959440X24001192-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Beyond ligand binding: Single molecule observation reveals how riboswitches integrate multiple signals to balance bacterial gene regulation 超越配体结合：单分子观察揭示了核糖开关如何整合多种信号以平衡细菌基因调控。
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2024-07-26 DOI: 10.1016/j.sbi.2024.102893
Adrien Chauvier, Nils G. Walter
{"title":"Beyond ligand binding: Single molecule observation reveals how riboswitches integrate multiple signals to balance bacterial gene regulation","authors":"Adrien Chauvier,&nbsp;Nils G. Walter","doi":"10.1016/j.sbi.2024.102893","DOIUrl":"10.1016/j.sbi.2024.102893","url":null,"abstract":"<div><p>Riboswitches are specialized RNA structures that orchestrate gene expression in response to sensing specific metabolite or ion ligands, mostly in bacteria. Upon ligand binding, these conformationally dynamic RNA motifs undergo structural changes that control critical gene expression processes such as transcription termination and translation initiation, thereby enabling cellular homeostasis and adaptation. Because RNA folds rapidly and co-transcriptionally, riboswitches make use of the low complexity of RNA sequences to adopt alternative, transient conformations on the heels of the transcribing RNA polymerase (RNAP), resulting in kinetic partitioning that defines the regulatory outcome. This review summarizes single molecule microscopy evidence that has begun to unveil a sophisticated network of dynamic, kinetically balanced interactions between riboswitch architecture and the gene expression machinery that, together, integrate diverse cellular signals.</p></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"88 ","pages":"Article 102893"},"PeriodicalIF":6.1,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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