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Current Opinion in Structural Biology

Shuai Zhao, Xingrun Zhang, Haitao Li
Histone post-translational modifications are crucial epigenetic mechanisms regulating a variety of biological events. Besides histone lysine acetylation, a repertoire of acylation types have been identified, including formylation, propionylation, butyrylation, crotonylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, succinylation, malonylation, glutarylation and benzoylation. From a structural perspective, here we summarize the writers and erasers of histone acylations and explain the molecular basis of these enzymes catalyzing non-acetyl histone acylations with a focus on histone crotonylation and β-hydroxybutyrylation...
November 1, 2018: Current Opinion in Structural Biology
Ylva Ivarsson, Per Jemth
It is becoming increasingly clear that eukaryotic cell physiology is largely controlled by protein-protein interactions involving disordered protein regions, which usually interact with globular domains in a coupled binding and folding reaction. Several protein recognition domains are part of large families where members can interact with similar peptide ligands. Because of this, much research has been devoted to understanding how specificity can be achieved. A combination of interface complementarity, interactions outside of the core binding site, avidity from multidomain architecture and spatial and temporal regulation of expression resolves the conundrum...
October 24, 2018: Current Opinion in Structural Biology
Monika Fuxreiter
Protein interactions are usually determined by well-defined contact patterns. In this scenario, structuring of the interface is a prerequisite, which takes place prior or coupled to binding. Recent data, however, indicate plasticity of the templated folding pathway as well as considerable variations: polymorphism or dynamics in the bound-state. Conformational fluctuations in both cases are modulated by non-native, transient contacts, which complement suboptimal binding motifs to improve affinity. Here I discuss both templated folding and fuzzy binding mechanisms and propose a uniform scheme...
October 16, 2018: Current Opinion in Structural Biology
Stefan Pfeffer, Julia Mahamid
Structural and cell biology have traditionally been separate disciplines and employed techniques that were well defined within the realm of either one or the other. Recent technological breakthroughs propelled electron microscopy of frozen hydrated specimens (cryo-EM) followed by single-particle analysis (SPA) to become a widely applied approach for obtaining near-atomic resolution structures of purified macromolecules. In parallel, ongoing developments on sample preparation are increasingly successful in bringing molecular views into cell biology...
October 16, 2018: Current Opinion in Structural Biology
Robert Abel, Eric S Manas, Richard A Friesner, Ramy S Farid, Lingle Wang
Drug discovery is widely recognized to be a difficult and costly activity in large part due to the challenge of identifying chemical matter which simultaneously optimizes multiple properties, one of which is affinity for the primary biological target. Further, many of these properties are difficult to predict ahead of expensive and time-consuming compound synthesis and experimental testing. Here we highlight recent work to develop compound affinity prediction models, and extensively investigate the value such models may provide to preclinical drug discovery...
October 12, 2018: Current Opinion in Structural Biology
Robert Schneider, Martin Blackledge, Malene Ringkjøbing Jensen
Advances in characterizing complexes of intrinsically disordered proteins (IDPs) have led to the discovery of a remarkably diverse interaction landscape that includes folding-upon-binding, highly dynamic complexes, multivalent interactions as well as regulatory switches controlled by post-translational modifications. Nuclear magnetic resonance (NMR) spectroscopy has in recent years made significant contributions to this field by describing the binding mechanisms and mapping conformational dynamics on multiple time scales...
October 10, 2018: Current Opinion in Structural Biology
Zhi-Qiang Xu, Nicholas E Dixon
Bacterial replisomes are dynamic multiprotein DNA replication machines that are inherently difficult for structural studies. However, breakthroughs continue to come. The structures of Escherichia coli DNA polymerase III (core)-clamp-DNA subcomplexes solved by single-particle cryo-electron microscopy in both polymerization and proofreading modes and the discovery of the stochastic nature of the bacterial replisomes represent notable progress. The structures reveal an intricate interaction network in the polymerase-clamp subassembly, providing insights on how replisomes may work...
October 4, 2018: Current Opinion in Structural Biology
Athi N Naganathan
A large body of work has gone into understanding the effect of mutations on protein structure and function. Conventional treatments have involved quantifying the change in stability, activity and relaxation rates of the mutants with respect to the wild-type protein. However, it is now becoming increasingly apparent that mutational perturbations consistently modulate the packing and dynamics of a significant fraction of protein residues, even those that are located >10-15 Å from the mutated site. Such long-range modulation of protein features can distinctly tune protein stability and the native conformational ensemble contributing to allosteric modulation of function...
September 27, 2018: Current Opinion in Structural Biology
Cameron Mura, Eli J Draizen, Philip E Bourne
Data science has emerged from the proliferation of digital data, coupled with advances in algorithms, software and hardware (e.g., GPU computing). Innovations in structural biology have been driven by similar factors, spurring us to ask: can these two fields impact one another in deep and hitherto unforeseen ways? We posit that the answer is yes. New biological knowledge lies in the relationships between sequence, structure, function and disease, all of which play out on the stage of evolution, and data science enables us to elucidate these relationships at scale...
September 26, 2018: Current Opinion in Structural Biology
Peter M Kasson, Shantenu Jha
Recent advances in both theory and computational power have created opportunities to simulate biomolecular processes more efficiently using adaptive ensemble simulations. Ensemble simulations are now widely used to compute a number of individual simulation trajectories and analyze statistics across them. Adaptive ensemble simulations offer a further level of sophistication and flexibility by enabling high-level algorithms to control simulations-based on intermediate results. We review some of the adaptive ensemble algorithms and software infrastructure currently in use and outline where the complexities of implementing adaptive simulation have limited algorithmic innovation to date...
September 25, 2018: Current Opinion in Structural Biology
Ewelina Guca, Yaser Hashem
Translation initiation in eukaryotes is a complex multistep process that requires the interplay of over a dozen protein factors together with the small ribosomal subunit (SSU) and the mRNA. During all these steps, the SSU serves as a platform for attachment, displacement and release of different molecules. In recent years, the great number of high-resolution X-ray and cryo-EM structures provided unprecedented insights into the molecular mechanism of this important process in eukaryotes. More specifically, cryo-EM became a leading technique in uncovering the structural details of this process due to exceptional advances in resolution and in image processing...
September 19, 2018: Current Opinion in Structural Biology
George A Cortina, Peter M Kasson
Beta-lactamase enzymes mediate the most common forms of gram-negative antibiotic resistance affecting clinical treatment. They also constitute an excellent model system for the difficult problem of understanding how allosteric mutations can augment catalytic activity of already-competent enzymes. Multiple allosteric mutations have been identified that alter catalytic activity or drug-resistance spectrum in class A beta lactamases, but predicting these in advance continues to be challenging. Here, we review computational techniques based on structure and/or molecular simulation to predict such mutations...
September 19, 2018: Current Opinion in Structural Biology
Hui Guo, John L Rubinstein
ATP synthases are rotary enzymes found in bacteria, chloroplasts, and mitochondria. These complexes produce the majority of cellular ATP in aerobic cells using energy from the transmembrane proton motive force established by the electron transport chain. In mitochondria, dimeric ATP synthase is essential for formation of the inner membrane cristae. While rotary catalysis in the soluble F1 region has been studied extensively by X-ray crystallography, the structure of the membrane embedded FO region remained elusive until recently...
September 18, 2018: Current Opinion in Structural Biology
Charlene M Kahler, Mitali Sarkar-Tyson, Emily A Kibble, Keith A Stubbs, Alice Vrielink
Society has benefitted greatly from the use of antibiotics. Unfortunately, the misuse of these valuable molecules has resulted in increased levels of antibiotic resistance, a major global and public health issue. This resistance and the reliance on a small number of biological targets for the development of antibiotics emphasizes the need for new targets. A critical aspect guiding the development of new antimicrobials through a rational structure-guided approach is to understand the molecular structures of specific biological targets of interest...
September 14, 2018: Current Opinion in Structural Biology
Romain Kooger, Piotr Szwedziak, Désirée Böck, Martin Pilhofer
The need for bacteria to interact with their environment has driven the evolution of elaborate secretion systems. By virtue of their function, secretion systems are macromolecular complexes associated with the cell envelope and therefore inherently difficult to study by conventional structural biology techniques. Cryo-electron microscopy (cryoEM) has become an invaluable technique to study large membrane-embedded complexes and led to major advances in the mechanistic understanding of secretion systems. CryoEM comprises of two main modalities, namely single particle analysis and tomography...
September 14, 2018: Current Opinion in Structural Biology
Yifan Cheng
In the past few years, significant technological breakthroughs in single particle cryo-electron microscopy enabled a 'resolution revolution' of this technique. It also changed structural biology in an unprecedented way. For many biological macromolecules, obtaining well-ordered crystals of suitable size is no longer a prerequisite for determining their atomic structures. One of the most impacted areas is the structural biology of integral membrane proteins. New structures are now determined at a rapid pace...
September 13, 2018: Current Opinion in Structural Biology
Kin Fan On, Matt Jaremko, Bruce Stillman, Leemor Joshua-Tor
No abstract text is available yet for this article.
September 12, 2018: Current Opinion in Structural Biology
Petrović Dušan, Kamerlin Shina Caroline Lynn
With increasing computational power, biomolecular simulations have become an invaluable tool for understanding enzyme mechanisms and the origins of enzyme catalysis. More recently, computational studies have started to focus on understanding how enzyme activity itself evolves, both in terms of enhancing the native or new activities on existing enzyme scaffolds, or completely de novo on previously non-catalytic scaffolds. In this context, both experiment and molecular modeling provided strong evidence for an important role of conformational dynamics in the evolution of enzyme functions...
September 8, 2018: Current Opinion in Structural Biology
Agnieszka Mateja, Robert J Keenan
Many tail-anchored (TA) membrane proteins are targeted to and inserted into the endoplasmic reticulum (ER) by the `guided entry of tail-anchored proteins' (GET) pathway. This post-translational pathway uses transmembrane-domain selective cytosolic chaperones for targeting, and a dedicated membrane protein complex for insertion. The past decade has seen rapid progress towards defining the molecular basis of TA protein biogenesis by the GET pathway. Here we review the mechanisms underlying each step of the pathway, emphasizing recent structural work and highlighting key questions that await future studies...
August 30, 2018: Current Opinion in Structural Biology
Shlomi Dvir, Amir Argoetti, Yael Mandel-Gutfreund
RNA-binding proteins (RBPs) interact with RNA to form Ribonucleoprotein Particles (RNPs). The interaction between RBPs and their RNA partners are traditionally thought to be mediated by highly conserved RNA-binding domains (RBDs). Recently, high-throughput studies led to the discovery of hundreds of novel proteins and domains, of which many do not follow the classical definition of RNA-binding. Despite technological innovations, experimental screenings are currently limited to the detection of specific types of RNPs, underscoring the importance of computational methods for predicting novel RBPs and RNA interacting residues and interfaces...
August 30, 2018: Current Opinion in Structural Biology
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