Current opinion in structural biology最新文献

Chromatin organization, facilitated by compartmentalization and loop extrusion, is crucial for proper gene expression and cell viability. Transcription has long been considered important for shaping genome architecture due to its pervasive activity across the genome and impact on the local chromatin environment. Although earlier studies suggested a minimal contribution of transcription to shaping global genome structure, recent insights from high-resolution chromatin contact mapping, polymer simulations, and acute perturbations have revealed its critical role in dynamic chromatin organization at the level of active genes and enhancer-promoter interactions. In this review, we discuss these latest advances, highlighting the direct interplay between transcriptional machinery and loop extrusion. Finally, we explore how transcription of genes and non-coding regulatory elements may contribute to the specificity of gene regulation, focusing on enhancers as sites of targeted cohesin loading.

The integration of artificial intelligence, machine learning and quantum computing into molecular dynamics simulations is catalyzing a revolution in computational biology, improving the accuracy and efficiency of simulations. This review describes the advancements and applications of these technologies to process vast molecular dynamics simulation datasets, adapt parameters of simulations and gain insight into complex biological processes. These advances include the use of predictive force fields, adaptive algorithms and quantum-assisted methodologies. While the integration of artificial intelligence and quantum computing with MD simulations provides insightful and stimulating improvements to our understanding of molecular mechanisms, it could introduce new issues related to data quality, interpretability of models and computational complexity. Modern multidisciplinary approaches are needed to navigate these challenges and exploit the potential of these emerging technologies for MD simulations of biomolecular systems.

Chromatin is a complex of DNA with histone proteins organized into nucleosomes that regulates genome accessibility and controls transcription, replication and repair by dynamically switching between open and compact states as a function of different parameters including histone post-translational modifications and interactions with chromatin modulators. Continuing advances in structural biology techniques including X-ray crystallography, cryo-electron microscopy and nuclear magnetic resonance (NMR) spectroscopy have facilitated studies of chromatin systems, in spite of challenges posed by their large size and dynamic nature, yielding important functional and mechanistic insights. In this review we highlight recent applications of magic angle spinning solid-state NMR – an emerging technique that is uniquely-suited toward providing atomistic information for rigid and flexible regions within biomacromolecular assemblies – to detailed characterization of structure, conformational dynamics and interactions for histone core and tail domains in condensed nucleosomes and oligonucleosome arrays mimicking chromatin at high densities characteristic of the cellular environment.

The application of single particle cryogenic electron microscopy (cryo-EM) to structure determination continues to have a transformative impact on our understanding on biological systems. While there has been a great deal of algorithmic development focused on improving attainable resolutions and streamlining atomic model building, there has not been commensurate development of validation metrics to ensure the accuracy of our cryo-EM maps and models. This review emphasizes the persistent issues that currently complicate single particle cryo-EM structure validation, and highlights the metrics that are gaining broad acceptance by the community. This article aims to underscore the need for further development of validation criteria and the potential role of machine learning methodologies in confidently assessing the quality of cryo-EM structures.

DNA mismatch repair (MMR) requires coordinated sequential actions of multiple proteins during a window of time after the replication apparatus makes an error and before the newly synthesized DNA undergoes chromosome compaction and/or methylation of dGATC sites in some γ-proteobacteria. In this review, we focus on the steps carried out by MutS and MutL homologs that initiate repair. We connect new structural data to early and recent single-molecule FRET and atomic force microscopy (AFM) studies to reveal insights into how signaling within the MMR cascade connects MutS homolog recognition of a mismatch to downstream repair. We present unified models of MMR initiation that account for the differences in the strand discrimination signals between methyl- and non-methyl-directed MMR.

RNAs are critical for complex cellular functions, characterized by their structural versatility and ability to undergo conformational transitions in response to cellular cues. The elusive structures of RNAs are being unraveled with unprecedented clarity, thanks to the technological advancements in structural biology, including nuclear magnetic resonance (NMR), X-ray crystallography, cryo-electron microscopy (cryo-EM) etc. This review focuses on examining the revolutionary impact of cryo-EM on our comprehension of RNA structural dynamics, underscoring the technique's contributions to structural biology and envisioning the future trajectory of this rapidly evolving field.

The membrane proximal external region (MPER) of the HIV envelope glycoproteins has generated renewed interest after a recent phase I vaccine trial that presented MPER lipid-peptide epitopes demonstrated promise to elicit a broad neutralization response. The antigenicity of MPER is intimately associated with the membrane, and its presentation relies significantly on the lipid composition. This review brings together recent findings on the influence of membranes on the conformation of MPER and its recognition by broadly neutralizing antibodies. Specifically, the review highlights the importance of properly accounting for the balance between protein–protein and membrane–protein interactions in vaccine design.

Since the onset of the COVID-19 pandemic, one productive area of research has focused on the intricate two- and three-dimensional structures taken on by SARS-CoV-2's RNA genome. These structures control essential viral processes, making them tempting targets for therapeutic intervention. This review focuses on two such structured regions, the frameshift stimulation element (FSE), which controls the translation of viral protein, and the 3′ untranslated region (3′ UTR), which is thought to regulate genome replication. For the FSE, we discuss its canonical pseudoknot's threaded and unthreaded topologies, as well as the diversity of competing two-dimensional structures formed by local and long-distance base pairing. For the 3′ UTR, we review the evidence both for and against the formation of its replication-enabling pseudoknot.

Splicing is a critical processing step during pre-mRNA maturation in eukaryotes. The correct selection of splice sites during the early steps of spliceosome assembly is highly important and crucial for the regulation of alternative splicing. Splice site recognition and alternative splicing depend on cis-regulatory sequence elements in the RNA and trans-acting splicing factors that recognize these elements and crosstalk with the canonical splicing machinery. Structural mechanisms involving early spliceosome complexes are governed by dynamic RNA structures, protein-RNA interactions and conformational flexibility of multidomain RNA binding proteins. Here, we highlight structural studies and integrative structural biology approaches, which provide complementary information from cryo-EM, NMR, small angle scattering, and X-ray crystallography to elucidate mechanisms in the regulation of early spliceosome assembly and quality control, highlighting the role of conformational dynamics.