Current opinion in structural biology最新文献

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HIV-1 gp160 in nanodiscs: Unravelling structures and guiding vaccine design 纳米圆盘中的HIV-1 gp160：揭示结构和指导疫苗设计

IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in structural biology

Pub Date : 2025-08-05 DOI: 10.1016/j.sbi.2025.103122

Nancy M. Elbaz, Mahmoud L. Nasr

The stabilization of HIV-1 gp160 trimers (Env) within phospholipid bilayer nanodiscs has provided critical structural insights into the membrane-proximal external region (MPER) and the broader dynamics of gp160. Cryo-EM and molecular simulations reveal that the membrane context preserves the MPER architecture and captures spontaneous trimer asymmetry, as well as ectodomain tilting. These dynamic properties expose vulnerable epitopes that are targeted by broadly neutralizing antibodies (bnAbs). Studies using nanodiscs have highlighted how interactions with the membrane affect the structure of gp160, the accessibility of epitopes, and the mechanisms of neutralization, providing important insights for immunogen design. Unlike soluble SOSIP and IDL constructs, full-length nanodisc-embedded gp160 maintains its native stability, flexibility, and the complete set of neutralization epitopes, suggesting that membrane-mimicking platforms are essential for the rational design of next-generation HIV vaccines targeting conserved regions, such as the MPER.

磷脂双层纳米圆盘内HIV-1 gp160三聚体（Env）的稳定为膜近端外区（MPER）和gp160更广泛的动力学提供了关键的结构见解。低温电镜和分子模拟表明，膜环境保留了MPER结构，并捕获了自发的三聚体不对称，以及外畴倾斜。这些动态特性暴露了易受攻击的表位，这些表位是广泛中和抗体（bnAbs）的目标。利用纳米片的研究强调了与膜的相互作用如何影响gp160的结构、表位的可及性和中和机制，为免疫原设计提供了重要的见解。与可溶性SOSIP和IDL构建物不同，全长纳米圆盘嵌入的gp160保持了其固有的稳定性、灵活性和完整的中和表位，这表明膜模拟平台对于合理设计针对保守区域（如MPER）的下一代HIV疫苗至关重要。

引用次数: 0

Frustration, dynamics, and catalysis 挫折，动力和催化

IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in structural biology

Pub Date : 2025-08-05 DOI: 10.1016/j.sbi.2025.103127

R. Gonzalo Parra , Diego U. Ferreiro

The controlled dissipation of chemical potentials is the fundamental way cells make a living. Enzyme-mediated catalysis allows the various transformations to proceed at biologically relevant rates with remarkable precision and efficiency. Theory, experiments, and computational studies coincide to show that local frustration is a useful concept to relate protein dynamics with catalytic power. Local frustration gives rise to the asperities of the energy landscapes that can harness the thermal fluctuations to guide the functional protein motions. We review here recent advances into these relationships from various fields of protein science. The biologically relevant dynamics is tuned by the evolution of protein sequences that modulate local frustration patterns to near-optimal values.

控制化学势的耗散是细胞生存的基本方式。酶介导的催化使各种转化以生物学相关的速度进行，具有显著的精度和效率。理论、实验和计算研究一致表明，局部挫折是一个有用的概念，将蛋白质动力学与催化力联系起来。局部挫折导致能量景观的凹凸不平，可以利用热波动来指导功能性蛋白质的运动。在此，我们回顾了蛋白质科学各个领域对这些关系的最新进展。生物相关的动态是通过蛋白质序列的进化来调节局部挫折模式到接近最佳值。

引用次数: 0

Optogenetic enzymes: A deep dive into design and impact 光遗传酶：深入研究设计和影响

IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in structural biology

Pub Date : 2025-08-05 DOI: 10.1016/j.sbi.2025.103126

Tanaya Basu Roy , Mana Heidari , Nikolay V. Dokholyan

Optogenetically regulated enzymes offer unprecedented spatiotemporal control over protein activity, intermolecular interactions, and intracellular signaling. Many design strategies have been developed for their fabrication based on the principles of intrinsic allostery, oligomerization or ‘split’ status, intracellular compartmentalization, and steric hindrance. In addition to employing photosensory domains as part of the traditional optogenetic toolset, the specificity of effector domains has also been leveraged for endogenous applications. Here, we discuss the dynamics of light activation while providing a bird's eye view of the crafting approaches, targets, and impact of optogenetic enzymes in orchestrating cellular functions, as well as the bottlenecks and an outlook into the future.

光遗传学调节酶提供了前所未有的时空控制蛋白质活性，分子间相互作用和细胞内信号。基于内在变构、寡聚或“分裂”状态、细胞内区隔化和空间位阻的原理，已经开发了许多设计策略。除了利用光敏结构域作为传统光遗传学工具集的一部分外，效应结构域的特异性也被用于内源性应用。在这里，我们讨论了光激活的动力学，同时提供了制作方法，目标和光遗传酶在协调细胞功能中的影响的鸟瞰图，以及瓶颈和对未来的展望。

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Orchestrating function: Concerted dynamics, allostery, and catalysis in protein tyrosine phosphatases 协调功能：蛋白酪氨酸磷酸酶的协调动力学、变构和催化作用。

IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in structural biology

Pub Date : 2025-08-04 DOI: 10.1016/j.sbi.2025.103125

Virgil A. Woods , Shivani Sharma , Alexis M. Lemberikman , Daniel A. Keedy

Protein tyrosine phosphatases (PTPs) are a family of enzymes that play critical roles in intracellular signaling and regulation. PTPs are conformationally dynamic, exhibiting motions of catalytic loops and additional regions of the structurally conserved catalytic domain. However, many questions remain about how dynamics contribute to catalysis and allostery in PTPs, how these behaviors vary among evolutionarily divergent PTP family members, and how mutations and ligands reshape dynamics to modulate PTP function. Recently, our understanding in these areas has expanded significantly, thanks to novel applications of existing methods and emergence of new approaches in structural biology and biophysics. Here we review exciting advances in this realm from the last few years. We organize our commentary both by experimental and computational methodologies, including solution techniques, avant-garde crystallography, molecular dynamics simulations, and bioinformatics, and also by scientific focus, including regulatory mechanisms, mutations and protein engineering, and small-molecule ligands such as allosteric modulators.

蛋白酪氨酸磷酸酶（PTPs）是一个在细胞内信号传导和调控中起关键作用的酶家族。PTPs是构象动态的，表现出催化环的运动和结构保守的催化域的附加区域。然而，关于动力学如何促进PTP的催化和变构，这些行为在进化不同的PTP家族成员中如何变化，以及突变和配体如何重塑动力学以调节PTP功能，仍然存在许多问题。最近，由于结构生物学和生物物理学中现有方法的新应用和新方法的出现，我们对这些领域的理解有了显著的扩展。在这里，我们回顾了过去几年在这一领域取得的令人兴奋的进展。我们通过实验和计算方法组织我们的评论，包括溶液技术，前卫晶体学，分子动力学模拟和生物信息学，以及科学焦点，包括调节机制，突变和蛋白质工程，以及小分子配体，如变构调节剂。

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引用次数: 0

Emerging paradigms in the lateral and transverse organization in biological membrane and their functional implications: Connecting the dots with biomolecular simulations 生物膜横向和横向组织的新范式及其功能含义：用生物分子模拟连接点

IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in structural biology

Pub Date : 2025-07-31 DOI: 10.1016/j.sbi.2025.103128

Anand Srivastava

Since the publication of the first papers in the early 1990s, molecular simulation as a reliable biophysical tool in the area of membrane biophysics has come a long way. Advances in simulation algorithms, coupled with exascale computing have pushed the size and time scales of biomolecular membrane simulations to scales where connections to experiments are made with higher fidelity. When integrated with experimental data in a theoretically well-grounded manner, current biomolecular simulations are providing indispensable insights that cannot be obtained through experiments alone. Here, I summarize some recent developments where simulations have allowed a deeper understanding in membrane spatiotemporal organization. I also discuss the need for transformative method developments to meet recent breakthroughs in experimental measurements at molecular scales.

自20世纪90年代初第一批论文发表以来，分子模拟作为一种可靠的生物物理工具在膜生物物理学领域取得了长足的发展。模拟算法的进步，加上百亿亿次计算，已经将生物分子膜模拟的大小和时间尺度推向了更高保真度的实验连接尺度。当以理论上有充分根据的方式与实验数据相结合时，当前的生物分子模拟提供了仅通过实验无法获得的不可或缺的见解。在这里，我总结了一些最近的发展，其中模拟允许对膜时空组织有更深的理解。我还讨论了变革方法发展的必要性，以满足最近在分子尺度上实验测量的突破。

引用次数: 0

Editorial overview of 3D genome chromatin organization and regulation 编辑概述三维基因组染色质组织和调控

IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in structural biology

Pub Date : 2025-07-30 DOI: 10.1016/j.sbi.2025.103123

Yuan He, Yawen Bai

引用次数: 0

Approaches for regulating enzyme activities: Recent advances in experiment and computation 调节酶活性的方法：实验和计算的最新进展

IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in structural biology

Pub Date : 2025-07-29 DOI: 10.1016/j.sbi.2025.103124

Qiang Cui

Major progress has been made in recent years in terms of strategies for regulating enzyme activities. Novel high-throughput enzyme kinetic assays and efficient computational methodologies enabled a deeper understanding of molecular mechanisms that dictate the activity of enzymes, which provide guidance to rational modulation of enzyme catalysis. Continued development of efficient screening, directed evolution technologies, and machine learning–driven protein engineering tools make it possible to tune enzyme activities without having to understand the detailed mechanism of catalysis regulation. By combining these two limiting approaches, the efficiency of enzyme regulation can be substantially improved as a mechanistic understanding can help reduce the size of design space before the ‘brute-force’ engineering approach takes over. We briefly discuss relevant advances in both experiment and computation and comment on future developments that can further enhance mechanistic understanding and engineering capability for broad applications.

近年来，在调节酶活性的策略方面取得了重大进展。新的高通量酶动力学分析和高效的计算方法使人们能够更深入地了解决定酶活性的分子机制，这为酶催化的合理调节提供了指导。高效筛选、定向进化技术和机器学习驱动的蛋白质工程工具的持续发展，使得无需了解催化调节的详细机制就可以调整酶的活性。通过结合这两种限制方法，酶调节的效率可以大大提高，因为在“暴力”工程方法接管之前，对机制的理解可以帮助减少设计空间的大小。我们简要地讨论了实验和计算的相关进展，并对未来的发展进行了评论，以进一步提高对机械的理解和工程能力，以实现广泛的应用。

引用次数: 0

A to-do list for realizing the sequence-to-function paradigm of proteins 实现蛋白质从序列到功能范式的待办事项清单

IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in structural biology

Pub Date : 2025-07-17 DOI: 10.1016/j.sbi.2025.103119

Chun Kit Chan , Christine Rajarigam , Patrick Jiang , Jacob Miratsky , Mustafa Demir , Melih Sener , Abhishek Singharoy

It has been a longstanding dream of the structural biology and molecular biophysics communities to determine protein functions directly from the amino acid sequences. Most methods available today, however, are homology- or library-based and often undermine determining divergent functions from comparable sequences or vice versa. The sequence-to-function relationship is intrinsically dependent on the biophysical space of protein dynamics, which can be potentially exploited to annotate function. But, despite three decades of active research, the space of molecular dynamics data remains grossly underpopulated. By employing surveys of the existing literature, we highlight this gray area in the context of machine learning methods. Thereafter, we share examples that point toward learning biophysical representations—or signatures—and combining them with integrative models as means to robustly associate sequence with function. The aim is to avoid having to compute protein dynamics for an impossible thousand years to achieve data completeness and generalization.

从氨基酸序列直接确定蛋白质的功能是结构生物学和分子生物物理学学界长期以来的梦想。然而，目前可用的大多数方法都是基于同源性或库的，并且经常破坏从可比序列中确定发散函数，反之亦然。序列-功能关系本质上依赖于蛋白质动力学的生物物理空间，这可以潜在地利用来注释功能。但是，尽管进行了三十年的积极研究，分子动力学数据的空间仍然严重不足。通过对现有文献的调查，我们强调了机器学习方法背景下的这一灰色地带。此后，我们将分享一些指向学习生物物理表征（或特征）的例子，并将它们与整合模型相结合，作为将序列与功能稳健关联的手段。其目的是避免为了实现数据的完整性和泛化而计算蛋白质动力学长达一千年。

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引用次数: 0

Editorial overview: Toward cellular-scale modeling: Bigger and disordered 编辑概述：向细胞尺度建模：更大和混乱

IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in structural biology

Pub Date : 2025-07-17 DOI: 10.1016/j.sbi.2025.103121

Yuji Sugita, Robert J. Woods

引用次数: 0

Multicolor single-molecule FRET studies on dynamic protein systems 动态蛋白质系统的多色单分子FRET研究

IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current opinion in structural biology

Pub Date : 2025-07-14 DOI: 10.1016/j.sbi.2025.103117

Ecenaz Bilgen, Don C. Lamb

Förster resonance energy transfer (FRET) is a powerful tool for studying protein conformations, interactions, and dynamics at the single-molecule level. Multicolor FRET extends conventional two-color FRET by incorporating three or more fluorophores and thereby enabling a more comprehensive view of complex biomolecular processes. This technique allows for the simultaneous tracking of multiple structural changes, detecting intermediate states, and resolving heterogeneous population distributions. In this review, we discuss the recent advancements in fluorophore labeling strategies and data analysis methods that have significantly improved the precision and applicability of multicolor FRET in protein studies. We then end this review by showcasing recent applications for investigating protein folding and processes involved in gene regulation.

Förster共振能量转移（FRET）是在单分子水平上研究蛋白质构象，相互作用和动力学的强大工具。多色FRET扩展传统的双色FRET纳入三个或更多的荧光团，从而使复杂的生物分子过程的更全面的看法。该技术允许同时跟踪多个结构变化，检测中间状态，并解决异质种群分布。在这篇综述中，我们讨论了荧光团标记策略和数据分析方法的最新进展，这些方法显著提高了多色FRET在蛋白质研究中的精度和适用性。然后，我们通过展示研究蛋白质折叠和基因调控过程的最新应用来结束这一综述。

引用次数: 0

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