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Current opinion in structural biology最新文献

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Resistance mutations, drug binding and drug residence times 耐药突变、药物结合和药物停留时间。
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2025-09-17 DOI: 10.1016/j.sbi.2025.103158
Ran Friedman
{"title":"Resistance mutations, drug binding and drug residence times","authors":"Ran Friedman","doi":"10.1016/j.sbi.2025.103158","DOIUrl":"10.1016/j.sbi.2025.103158","url":null,"abstract":"<div><div>The rapid evolution of microorganisms and cancer cells makes it difficult to treat tumours and infectious diseases, because resistance to drugs is the rule rather than the exception. Structures or models of protein–drug complexes help to understand how mutations lead to resistance and to design better drugs. However, it is difficult to reason how small changes in the structure lead to drug resistance. Thus, protein and drug dynamics need to be considered. Strategies to increase drug residence are sought after to increase the efficacy of drugs. Computational methods to calculate the effect of mutations on drug binding and residence times are being developed and improved, but are challenging. A priori prediction of a mutation's effect on drug binding is an even greater challenge. On the other hand, knowledge about protein–drug complexes has led to the development of multiple design strategies that aim to reduce mutation-driven drug resistance.</div></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"95 ","pages":"Article 103158"},"PeriodicalIF":6.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085329","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
From snapshots to ensembles: Integrating experimental data and dynamics 从快照到集成：整合实验数据和动力学
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2025-09-15 DOI: 10.1016/j.sbi.2025.103155
Vanessa Leone , Fabrizio Marinelli
{"title":"From snapshots to ensembles: Integrating experimental data and dynamics","authors":"Vanessa Leone ,&nbsp;Fabrizio Marinelli","doi":"10.1016/j.sbi.2025.103155","DOIUrl":"10.1016/j.sbi.2025.103155","url":null,"abstract":"<div><div>Protein function arises from the interplay of structure, dynamics, and biomolecular interactions. Despite advances in cryo-EM and AI-based structure prediction, capturing dynamic and energetic features remains a challenge. Biophysical methods like NMR, EPR, HDX-MS, SAXS, and cryo-EM provide valuable but often indirect signals. Connecting these to molecular mechanisms requires integrative approaches that combine experiments with physics-based simulations, revealing both stable structures and transient, functionally important intermediates. This review highlights recent advances in integrative modeling using the maximum entropy principle to build dynamic ensembles from diverse data while addressing uncertainty and bias. These methods help resolve heterogeneity and interpret low-resolution data. We conclude by exploring how integrative modeling, enhanced sampling, and AI-driven tools enable new insights into slow, large-scale conformational changes.</div></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"95 ","pages":"Article 103155"},"PeriodicalIF":6.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060742","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
Editorial overview: Artificial intelligence methodologies in structural biology 编辑概述：结构生物学中的人工智能方法
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2025-09-13 DOI: 10.1016/j.sbi.2025.103156
Chaok Seok, Pratyush Tiwary
{"title":"Editorial overview: Artificial intelligence methodologies in structural biology","authors":"Chaok Seok,&nbsp;Pratyush Tiwary","doi":"10.1016/j.sbi.2025.103156","DOIUrl":"10.1016/j.sbi.2025.103156","url":null,"abstract":"","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"95 ","pages":"Article 103156"},"PeriodicalIF":6.1,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145047694","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
Toward understanding whole enzymatic reaction cycles using multi-scale molecular simulations 利用多尺度分子模拟来理解整个酶促反应循环
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2025-09-11 DOI: 10.1016/j.sbi.2025.103153
Shingo Ito , Chigusa Kobayashi , Kiyoshi Yagi , Yuji Sugita
{"title":"Toward understanding whole enzymatic reaction cycles using multi-scale molecular simulations","authors":"Shingo Ito ,&nbsp;Chigusa Kobayashi ,&nbsp;Kiyoshi Yagi ,&nbsp;Yuji Sugita","doi":"10.1016/j.sbi.2025.103153","DOIUrl":"10.1016/j.sbi.2025.103153","url":null,"abstract":"<div><div>Enzymes effectively catalyze chemical reactions at their active sites. The reactions involve three microscopic events at the active sites: substrate binding, multi-step chemical reactions, and product release. These events are often coupled with enzyme conformational changes, making theoretical and computational analyses more challenging. Advanced molecular simulations, involving molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM), are now utilized to investigate the functions of enzymes such as tryptophan synthase and P-type ATPases. Here, we summarize recent multiscale molecular simulations that incorporate multiple microscopic events in enzyme functions. The coupling of enzyme conformational changes and chemical reactions can predict a proper direction in enzymatic reaction cycles, which requires accurate predictions of the free energy changes between different physiological states. Using machine learning (ML) methods, all the microscopic events in enzyme catalysis could be described with the same accuracy as quantum chemistry. We also discuss recent developments in ML/MM simulations for enzyme catalysis.</div></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"95 ","pages":"Article 103153"},"PeriodicalIF":6.1,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145047693","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
Computational modeling of protein–ligand interactions: From binding site identification to pose prediction and beyond 蛋白质-配体相互作用的计算模型：从结合位点鉴定到姿态预测及其他
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2025-09-10 DOI: 10.1016/j.sbi.2025.103152
Viet-Khoa Tran-Nguyen, Anne-Claude Camproux
{"title":"Computational modeling of protein–ligand interactions: From binding site identification to pose prediction and beyond","authors":"Viet-Khoa Tran-Nguyen,&nbsp;Anne-Claude Camproux","doi":"10.1016/j.sbi.2025.103152","DOIUrl":"10.1016/j.sbi.2025.103152","url":null,"abstract":"<div><div>Protein-ligand modeling is a cornerstone of modern drug discovery, facilitating the identification and optimization of bioactive compounds that modulate protein function. Computational approaches provide cost-effective and scalable strategies for exploring the growing chemical and biological spaces, accelerating early-stage drug development. Advances in both physics-based methods and data-driven machine learning techniques have expanded the range and accuracy of tools available for modeling protein-ligand interactions. This review provides a current and concise view of key methodologies in protein-ligand modeling, including binding site prediction and the generation and evaluation of target-bound ligand conformations. It also discusses state-of-the-art machine learning approaches that are reshaping how these tasks are performed and enhancing the accuracy of binding site, binding pose, and binding affinity predictions.</div></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"95 ","pages":"Article 103152"},"PeriodicalIF":6.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145027162","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
Dynamic characteristics of proteolysis-targeting chimera systems revealed by in silico computations 用计算机计算揭示蛋白水解靶向嵌合体系统的动态特性。
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2025-09-10 DOI: 10.1016/j.sbi.2025.103151
Kexin Xu , Jingxuan Ge , Rongfan Tang , Tingjun Hou , Huiyong Sun
{"title":"Dynamic characteristics of proteolysis-targeting chimera systems revealed by in silico computations","authors":"Kexin Xu ,&nbsp;Jingxuan Ge ,&nbsp;Rongfan Tang ,&nbsp;Tingjun Hou ,&nbsp;Huiyong Sun","doi":"10.1016/j.sbi.2025.103151","DOIUrl":"10.1016/j.sbi.2025.103151","url":null,"abstract":"<div><div>Proteolysis-targeting chimeras (PROTACs) achieve irreversible clearance of target proteins by hijacking the ubiquitin–proteasome system, breaking the design paradigm of traditional inhibitory drugs. The development of computational approaches has effectively promoted the rational design of PROTACs, yet existing methods mainly focus on predicting the static structure of PROTAC systems, with methodological gaps in analyzing their dynamic characteristics. Knowing that the dynamic behaviors can dramatically influence the stability and degradation efficacy of a PROTAC system, we systematically summarize the recent progresses of using structure-based and structure–artificial intelligence–hybrid methodologies for characterizing the dynamic behaviors of PROTAC systems, with a focus on elucidating the dynamic characteristics of target protein–PROTAC–E3 ligase ternary structures and prediction of their key properties.</div></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"95 ","pages":"Article 103151"},"PeriodicalIF":6.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039512","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
Ras/Raf dimerization model for activation of Raf kinase 激活Raf激酶的Ras/Raf二聚化模型
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2025-09-09 DOI: 10.1016/j.sbi.2025.103150
Marcela de Barros, Gregory Labrie, Carla Mattos
{"title":"Ras/Raf dimerization model for activation of Raf kinase","authors":"Marcela de Barros,&nbsp;Gregory Labrie,&nbsp;Carla Mattos","doi":"10.1016/j.sbi.2025.103150","DOIUrl":"10.1016/j.sbi.2025.103150","url":null,"abstract":"<div><div>Our previously proposed Ras dimerization model is consistent with recent details observed by NMR in that Raf activation is centered on the Ras/Raf dimer, distinct from one in which Ras activates Raf as a monomer with the Raf cysteine rich domain inserted in the membrane. We review mechanistic understanding of Raf activation within nanoclusters of Ras on the membrane, with a shift to dimers upon binding Raf. This sets the stage for a signaling platform composed of Ras/Raf and Galectin dimers that facilitates the release of Raf autoinhibition and folding of the Raf intrinsically disordered region between the Ras-binding domains and the kinase bound to 14-3-3 and MEK. This platform could provide synchronized units for signal amplification and is consistent with a Ras stationary phase observed in cells.</div></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"95 ","pages":"Article 103150"},"PeriodicalIF":6.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020928","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
How residence time works in allosteric drugs 在变构药中停留时间是如何起作用的
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2025-08-29 DOI: 10.1016/j.sbi.2025.103149
Ruth Nussinov , Hyunbum Jang
{"title":"How residence time works in allosteric drugs","authors":"Ruth Nussinov ,&nbsp;Hyunbum Jang","doi":"10.1016/j.sbi.2025.103149","DOIUrl":"10.1016/j.sbi.2025.103149","url":null,"abstract":"<div><div>Drug residence time defines the duration the drug is bound to its protein target. It is a crucial determinant of drug action. Yet, <em>a priori</em> estimating it in the design could be the most challenging. The mechanisms of allosteric and orthosteric drugs differ in how they affect it. Binding at the active site, the residence time of orthosteric drugs is primarily affected by binding kinetics, which is not the case for allosteric drugs. Allosteric drugs determine the orthosteric drug residence time by the nature and extent of the population shift that they promote, which modulate the active site conformation. However, cooperative binding is bidirectional; orthosteric drug binding at the active site can increase (decrease) residence time at the allosteric site.</div></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"94 ","pages":"Article 103149"},"PeriodicalIF":6.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913149","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
Recent advances in quantifying protein conformational ensembles with dipolar EPR spectroscopy 偶极EPR光谱定量蛋白质构象群的最新进展
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2025-08-23 DOI: 10.1016/j.sbi.2025.103139
Reza Dastvan , Stefan Stoll
{"title":"Recent advances in quantifying protein conformational ensembles with dipolar EPR spectroscopy","authors":"Reza Dastvan ,&nbsp;Stefan Stoll","doi":"10.1016/j.sbi.2025.103139","DOIUrl":"10.1016/j.sbi.2025.103139","url":null,"abstract":"<div><div>This perspective highlights recent applications and technological progress in dipolar electron paramagnetic resonance (EPR) spectroscopy, including double electron–electron resonance (DEER) spectroscopy. These methods provide nanoscale distance distributions between site-specific spin labels in biomacromolecules. The resulting data are particularly well suited for quantifying the structure and energetics of conformational ensembles of multi-state and flexible proteins. Recent applications span a wide range of systems and are accompanied by innovations in spin labeling, deuteration, in-cell measurements, integrative multi-technique approaches, and novel computational modeling methods combined with structure prediction tools.</div></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"94 ","pages":"Article 103139"},"PeriodicalIF":6.1,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889508","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
Cryo-focused ion beam milling for cryo-electron tomography: Shaping the future of in situ structural biology 低温聚焦离子束铣削用于低温电子断层扫描：塑造原位结构生物学的未来
IF 6.1 2区 生物学
Current opinion in structural biology Pub Date : 2025-08-22 DOI: 10.1016/j.sbi.2025.103138
Sven Klumpe , Jürgen M. Plitzko
{"title":"Cryo-focused ion beam milling for cryo-electron tomography: Shaping the future of in situ structural biology","authors":"Sven Klumpe ,&nbsp;Jürgen M. Plitzko","doi":"10.1016/j.sbi.2025.103138","DOIUrl":"10.1016/j.sbi.2025.103138","url":null,"abstract":"<div><div>Cryo-focused ion beam instruments to produce cellular thin sections for subsequent imaging by cryo-electron tomography have become an integral part of the methodologies for <em>in situ</em> structural biology, enabling high-resolution imaging of biological structures in their native environment. The application of these instruments has opened windows into cells that allowed unprecedented insights into the ultrastructure of cells and more recently, small multicellular organisms and tissues. While great strides have been made in the characterization of cryo-FIB milling and the streamlining of workflows with these tools, many limitations and technical challenges remain to be resolved. Here, we discuss the technical and technological challenges ahead to continue the steep rise of biological discoveries by in-cell cryo-electron tomography to enable cellular structural biology in the multicellular context.</div></div>","PeriodicalId":10887,"journal":{"name":"Current opinion in structural biology","volume":"94 ","pages":"Article 103138"},"PeriodicalIF":6.1,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889509","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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