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Current Opinion in Structural Biology

Aneth S Canale, Pamela A Cote-Hammarlof, Julia M Flynn, Daniel Na Bolon
Biology has, and continues to be, shaped by evolutionary mechanisms. Within the past decade, local fitness landscapes have become experimentally tractable and are providing new perspectives on evolutionary mechanisms. Powered by next-generation sequencing, the impacts of all individual amino acid substitutions on function have been quantified for dozens of proteins. These fitness maps have been utilized to investigate the biophysical underpinnings of existing protein function as well as the appearance and enhancement of new protein functions...
January 16, 2018: Current Opinion in Structural Biology
Philipp Bieri, Basil J Greber, Nenad Ban
Mitochondrial ribosomes (mitoribosomes) almost exclusively synthesize essential components of the oxidative phosphorylation machinery. Dysfunction of mitochondrial protein biosynthesis leads to human diseases and plays an important role in the altered metabolism of cancer cells. Recent developments in cryo-electron microscopy enabled the structural characterization of complete yeast and mammalian mitoribosomes at near-atomic resolution. Despite originating from ancestral bacterial ribosomes, mitoribosomes have diverged in their composition and architecture...
January 15, 2018: Current Opinion in Structural Biology
Nehru Viji Sankaranarayanan, Balaji Nagarajan, Umesh R Desai
Glycosaminoglycans (GAGs) play key roles in virtually all biologic responses through their interaction with proteins. A major challenge in understanding these roles is their massive structural complexity. Computational approaches are extremely useful in navigating this bottleneck and, in some cases, the only avenue to gain comprehensive insight. We discuss the state-of-the-art on computational approaches and present a flowchart to help answer most basic, and some advanced, questions on GAG-protein interactions...
January 9, 2018: Current Opinion in Structural Biology
David Ochoa, David Bradley, Pedro Beltrao
Protein kinases are central regulators of most eukaryotic cellular processes. While kinase signalling has been studied for decades, only through recent advances in mass spectrometry have we been able to identify phophosites in large scale and quantify their regulation across conditions. These advances are challenging our understanding of kinase signalling and shedding light into how these systems have evolved. Kinase substrate specificity appears to be strongly conserved but their target phosphosites diverge at a very fast rate...
January 6, 2018: Current Opinion in Structural Biology
Tien K Nguyen, Takafumi Ueno
Recent achievements in development of protein assembles within cells have extended biosupramolecular composites into a new era with versatile applications in the fields of biomaterial and biotechnology. Using methods with biological and physicochemical routes has made this era of research more interesting and challenging. Further advances in protein engineering have facilitated efficient fabrication of supramolecular complexes within living cells. Here, we provide a review of recent efforts to engineer protein assemblies within cells and describe the promising properties of these assemblies...
January 6, 2018: Current Opinion in Structural Biology
Ho Yee Joyce Fung, Melissa Birol, Elizabeth Rhoades
Intrinsically disordered proteins (IDPs) have critical roles in a diverse array of cellular functions. Of relevance here is that they are components of macromolecular complexes, where their conformational flexibility helps mediate interactions with binding partners. IDPs often interact with their binding partners through short sequence motifs, commonly repeated within the disordered regions. As such, multivalent interactions are common for IDPs and their binding partners within macromolecular complexes. Here we discuss the importance of IDP multivalency in three very different macromolecular assemblies: biomolecular condensates, the nuclear pore, and the cytoskeleton...
January 4, 2018: Current Opinion in Structural Biology
Anna Laddach, Joseph Chi-Fung Ng, Sun Sook Chung, Franca Fraternali
We review recent progress in the mapping of genetic variants to proteins, in the context of their interactions, as measured from experiments and/or computational predictions. Such variants can impact on the molecular mechanisms underlying an interaction and its stability. We highlight recent work which relies on the effective use of protein-protein interaction networks (PPINs), integrated with 3D structural information, for evaluating disease-associated variants. Furthermore, we discuss how the integration of multiple layers of biological information, in the context of PPINs, can improve the interpretation of genetic variants and inspire new therapeutic strategies...
January 4, 2018: Current Opinion in Structural Biology
Michael H Hecht, Shlomo Zarzhitsky, Christina Karas, Sarangan Chari
Natural proteins represent a minuscule fraction of possible sequence space. These very rare sequences display remarkable properties: They fold into many different stable structures, and perform a wide range of complex biological functions. These two considerations-rarity and functionality-may suggest that natural proteins are somehow special. Is this true? We address this question by exploring attempts to recapitulate the special structures and functions of natural proteins into sequences designed de novo.
January 3, 2018: Current Opinion in Structural Biology
Sandhya P Tiwari, Nathalie Reuter
The intrinsic dynamics of proteins has been suggested to be the most conserved compared to its sequence or structure. As such, the contributing factors to the conservation of dynamics have yet to be determined definitively. Some have suggested that function drives the conservation of protein flexibility, while others have indicated that the overall topology determines protein flexibility patterns. In general, many characteristic features of protein flexibility can be derived from simple coarse-grained models whose success rests on the link between protein local packing density and flexibility...
December 26, 2017: Current Opinion in Structural Biology
Veronika Sachsenhauser, James Ca Bardwell
Recently, several innovative approaches have been developed that allow one to directly screen or select for improved protein folding in the cellular context. These methods have the potential of not just leading to a better understanding of the in vivo folding process, they may also allow for improved production of proteins of biotechnological interest.
December 23, 2017: Current Opinion in Structural Biology
Ralf P Richter, Natalia S Baranova, Anthony J Day, Jessica Cf Kwok
Conventional wisdom has it that proteins fold and assemble into definite structures, and that this defines their function. Glycosaminoglycans (GAGs) are different. In most cases the structures they form have a low degree of order, even when interacting with proteins. Here, we discuss how physical features common to all GAGs-hydrophilicity, charge, linearity and semi-flexibility-underpin the overall properties of GAG-rich matrices. By integrating soft matter physics concepts (e.g. polymer brushes and phase separation) with our molecular understanding of GAG-protein interactions, we can better comprehend how GAG-rich matrices assemble, what their properties are, and how they function...
December 21, 2017: Current Opinion in Structural Biology
Andrew Almond
Glycosaminoglycans are long unbranched and complex polysaccharides that are an essential component of mammalian extracellular matrices. Characterization of their molecular structure, dynamics and interactions are essential to understand important biological phenomena in health and disease, and will lead to novel therapeutics and medical devices. However, this has proven to be a challenge experimentally and theoretical techniques are needed to develop new hypotheses, and interpret experiments. This review aims to examine the current theoretical (rather than experimental) methods used by researchers to investigate glycosaminoglycan structure, dynamics and interactions, from the monosaccharide to the macromolecular scale...
December 15, 2017: Current Opinion in Structural Biology
Matilda S Newton, Vickery L Arcus, Monica L Gerth, Wayne M Patrick
Enzymes have been evolving to catalyze new chemical reactions for billions of years, and will continue to do so for billions more. Here, we review examples in which evolutionary biochemists have used big data and high-throughput experimental tools to shed new light on the enormous functional diversity of extant enzymes, and the evolutionary processes that gave rise to it. We discuss the role that gene loss has played in enzyme evolution, as well as the more familiar processes of gene duplication and divergence...
December 2, 2017: Current Opinion in Structural Biology
Lars V Bock, Michal H Kolář, Helmut Grubmüller
The ribosome is a macromolecular complex which is responsible for protein synthesis in all living cells according to their transcribed genetic information. Using X-ray crystallography and, more recently, cryo-electron microscopy (cryo-EM), the structure of the ribosome was resolved at atomic resolution in many functional and conformational states. Molecular dynamics simulations have added information on dynamics and energetics to the available structural information, thereby have bridged the gap to the kinetics obtained from single-molecule and bulk experiments...
December 1, 2017: Current Opinion in Structural Biology
Vikram Alva, Andrei N Lupas
The diversity of modern proteins arose through the combinatorial shuffling and differentiation of a limited number of autonomously folding domain prototypes, but the origin of these prototypes themselves has long remained poorly understood. In recent years, the proposal that they originated by repetition, accretion, and recombination from an ancestral set of peptides, which evolved as cofactors of RNA-based replication and catalysis, has gained wide acceptance, supported by the systematic identification of such ancestral peptides and the experimental recapitulation of the mechanisms by which they could have yielded the first folded proteins...
November 28, 2017: Current Opinion in Structural Biology
Jochen S Hub
Small-angle and wide-angle X-ray scattering in solution (SAXS, WAXS, SWAXS) is an increasingly accurate method for obtaining information on biomolecular structures, ensembles, and time-resolved dynamics at near-native conditions. However, the interpretation of the solution scattering data by computational methods is complicated by the low information content of the data, by scattering contributions from the hydration layer, and by unknown systematic errors. In the light of available computational methods, we first review the main computational challenges with the interpretation of SWAXS data...
November 20, 2017: Current Opinion in Structural Biology
Paweł Śledź, Amedeo Caflisch
Recent years have witnessed rapid developments of computer-aided drug design methods, which have reached accuracy that allows their routine practical applications in drug discovery campaigns. Protein structure-based methods are useful for the prediction of binding modes of small molecules and their relative affinity. The high-throughput docking of up to 106 small molecules followed by scoring based on implicit-solvent force field can robustly identify micromolar binders using a rigid protein target. Molecular dynamics with explicit solvent is a low-throughput technique for the characterization of flexible binding sites and accurate evaluation of binding pathways, kinetics, and thermodynamics...
November 14, 2017: Current Opinion in Structural Biology
Anna Pabis, Valeria A Risso, Jose M Sanchez-Ruiz, Shina Cl Kamerlin
Enzymes are flexible catalysts, and there has been substantial discussion about the extent to which this flexibility contributes to their catalytic efficiency. What has been significantly less discussed is the extent to which this flexibility contributes to their evolvability. Despite this, recent years have seen an increasing number of both experimental and computational studies that demonstrate that cooperativity and flexibility play significant roles in enzyme innovation. This review covers key developments in the field that emphasize the importance of enzyme dynamics not just to the evolution of new enzyme function(s), but also as a property that can be harnessed in the design of new artificial enzymes...
November 12, 2017: Current Opinion in Structural Biology
Yong Wang, Katrine Bugge, Birthe B Kragelund, Kresten Lindorff-Larsen
Cells are dependent on transmembrane receptors to communicate and transform chemical and physical signals into intracellular responses. Because receptors transport 'information', conformational changes and protein dynamics play a key mechanistic role. We here review examples where experiment and computation have been used to study receptor dynamics. Recent studies on three distinct classes of receptors (G-protein coupled receptors, ligand-gated ion-channels and single-pass receptors) are highlighted to show that conformational changes across a range of time-scales and length-scales are central to function...
November 11, 2017: Current Opinion in Structural Biology
Neil J Bruce, Gaurav K Ganotra, Daria B Kokh, S Kashif Sadiq, Rebecca C Wade
The recent and growing evidence that the efficacy of a drug can be correlated to target binding kinetics has seeded the development of a multitude of novel methods aimed at computing rate constants for receptor-ligand binding processes, as well as gaining an understanding of the binding and unbinding pathways and the determinants of structure-kinetic relationships. These new approaches include various types of enhanced sampling molecular dynamics simulations and the combination of energy-based models with chemometric analysis...
November 10, 2017: Current Opinion in Structural Biology
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