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Current Opinion in Structural Biology

Erhard Hohenester
A unique O-mannose-linked glycan on the transmembrane protein dystroglycan binds a number of extracellular matrix proteins containing laminin G-like (LG) domains. The dystroglycan-matrix interaction is essential for muscle function: disrupted biosynthesis of the matrix-binding modification causes several forms of muscular dystrophy. The complete chemical structure of this modification has been deciphered in the past few years. We now know that LG domains bind to a glycosaminoglycan-like polysaccharide of [-3GlcAβ1,3Xylα1-] units, termed matriglycan, that is attached to a highly unusual heptasaccharide linker...
December 6, 2018: Current Opinion in Structural Biology
Grigoriy A Armeev, Anna K Gribkova, Iunona Pospelova, Galina A Komarova, Alexey K Shaytan
Nucleosomes are fundamental units of chromatin compaction, which organize ∼200 DNA base pairs using an octamer of histone proteins. Their ubiquitous presence in the cell nucleus since the first eukaryotes compelled the chromatin machinery to coevolve and learn how to exploit various modes of nucleosome dynamics and sense differences in nucleosome composition. Alterations to histone or DNA sequences, post-translational modifications (PTM) of histones, recruitment of chromatin proteins modulate nucleosome dyn amics and provide epigenetic regulation to the DNA processing pathways (transcription, replication, repair, etc...
December 4, 2018: Current Opinion in Structural Biology
J L Vilas, N Tabassum, J Mota, D Maluenda, A Jiménez-Moreno, T Majtner, J M Carazo, S T Acton, C O S Sorzano
Electron cryomicroscopy (cryo-EM) is essential for the study and functional understanding of non-crystalline macromolecules such as proteins. These molecules cannot be imaged using X-ray crystallography or other popular methods. Cryo-EM has been successfully used to visualize molecules such as ribosomes, viruses, and ion channels, for example. Obtaining structural models of these at various conformational states leads to insight on how these molecules function. Recent advances in imaging technology have given cryo-EM a scientific rebirth...
November 30, 2018: Current Opinion in Structural Biology
Alexander J Pak, Gregory A Voth
Recent progress in coarse-grained (CG) molecular modeling and simulation has facilitated an influx of computational studies on biological macromolecules and their complexes. Given the large separation of length-scales and time-scales that dictate macromolecular biophysics, CG modeling and simulation are well-suited to bridge the microscopic and mesoscopic or macroscopic details observed from all-atom molecular simulations and experiments, respectively. In this review, we first summarize recent innovations in the development of CG models, which broadly include structure-based, knowledge-based, and dynamics-based approaches...
November 30, 2018: Current Opinion in Structural Biology
Massimiliano Bonomi, Michele Vendruscolo
Achieving a comprehensive understanding of the behaviour of proteins is greatly facilitated by the knowledge of their structures, thermodynamics and dynamics. All this information can be provided in an effective manner in terms of structural ensembles. A structural ensemble can be obtained by determining the structures, populations and interconversion rates for all the main states that a protein can occupy. To reach this goal, integrative methods that combine experimental and computational approaches provide powerful tools...
November 28, 2018: Current Opinion in Structural Biology
Marie-France Langelier, Travis Eisemann, Amanda A Riccio, John M Pascal
Poly(ADP-ribose) is a posttranslational modification and signaling molecule that regulates many aspects of human cell biology, and it is synthesized by enzymes known as poly(ADP-ribose) polymerases, or PARPs. A diverse collection of domain structures dictates the different cellular roles of PARP enzymes and regulates the production of poly(ADP-ribose). Here we primarily review recent structural insights into the regulation and catalysis of two family members: PARP-1 and Tankyrase. PARP-1 has multiple roles in the cellular response to DNA damage and the regulation of gene transcription, and Tankyrase regulates a diverse set of target proteins involved in cellular processes such as mitosis, genome integrity, and cell signaling...
November 24, 2018: Current Opinion in Structural Biology
Laura Wood, Gavin J Wright
Thousands of secreted factors and plasma membrane-associated cell surface receptors are categorised into families that vary widely in their structures and functions. They often participate in extracellular binding events, but due to their unique physicochemical properties, their interactions are challenging to study. As lists of extracellular proteins become more complete and accurate, new methodologies are being developed to systematically identify how these proteins interact. Two main approaches have been used: direct binding between recombinant soluble receptor ectodomains and cell-based assays...
November 20, 2018: Current Opinion in Structural Biology
Enrico Guarnera, Igor N Berezovsky
Regardless of the diversity of systems, allosteic signalling is found to be always caused by perturbations. This recurring trait of allostery serves as a foundation for developing different experimental efforts and theoretical models for the studies of allosteric mechanisms. Among computational approaches considered here particular emphasis is given to the structure-based statistical mechanical model of allostery (SBSMMA), which allows one to study the causality and energetics of allosteric communication. We argue that the reverse allosteric signaling on the basis of SBSMMA can be used for predicting latent allosteric sites and inducing a tunable allosteric response...
November 12, 2018: Current Opinion in Structural Biology
E Sila Ozdemir, Ruth Nussinov, Attila Gursoy, Ozlem Keskin
Proteins are dynamic, and this holds especially for their surfaces. They display ensembles of conformations, which allows them to interact with diverse partners, often via the same patch of surface, and execute their distinct functions. Binding a specific partner can stimulate - or suppress - a distinct signaling pathway. This diversity poses a challenge: how to reliably model a specific protein-protein interaction (PPI)? This problem is compounded in protein assemblies, which are typically large, involving multiple protein-protein interfaces...
November 12, 2018: Current Opinion in Structural Biology
Kiersten M Ruff, Rohit V Pappu, Alex S Holehouse
While many proteins and protein regions utilize a complex repertoire of amino acids to achieve their biological function, a subset of protein sequences are enriched in a reduced set of amino acids. These so-called low complexity (LC) sequences, specifically intrinsically disordered variants of LC sequences, have been the focus of recent investigations owing to their roles in a range of biological functions, specifically phase separation. Computational studies of LC sequences have provided rich insights into their behavior both as individual proteins in dilute solutions and as the drivers and modulators of higher-order assemblies...
November 12, 2018: 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
Dinshaw Patel, Eric Westhof
No abstract text is available yet for this article.
December 2018: Current Opinion in Structural Biology
Alice Vrielink, Hazel M Holden
No abstract text is available yet for this article.
December 2018: Current Opinion in Structural Biology
Heng Ru, Pengfei Zhang, Hao Wu
A hallmark of vertebrate immunity is the diverse repertoire of antigen-receptor genes that results from combinatorial splicing of gene coding segments by V(D)J recombination. The (RAG1-RAG2)2 endonuclease complex (RAG) specifically recognizes and cleaves a pair of recombination signal sequences (RSSs), 12-RSS and 23-RSS, via the catalytic steps of nicking and hairpin formation. Both RSSs immediately flank the coding end segments and are composed of a conserved heptamer, a conserved nonamer, and a non-conserved spacer of either 12 base pairs (bp) or 23 bp in between...
December 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
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