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Current Opinion in Structural Biology

David M Thal, Ziva Vuckovic, Christopher J Draper-Joyce, Yi-Lynn Liang, Alisa Glukhova, Arthur Christopoulos, Patrick M Sexton
G protein-coupled receptors (GPCRs) are the largest superfamily of cell surface receptor proteins and are important drug targets for many human diseases. In the last decade, remarkable progress has been made in the determination of atomic structures of GPCRs with over 200 structures from 53 unique receptors having been solved. Technological advances in protein engineering and X-ray crystallography have driven much of the progress to date. However, recent advances in cryo-electron microscopy have facilitated the structural determination of three new structures of active-state GPCRs in complex with heterotrimeric G protein...
March 13, 2018: Current Opinion in Structural Biology
Tingting Wang, Xiaotong Fan, Chunxi Hou, Junqiu Liu
Enzymes are biomacromolecules with three-dimensional structures composed of peptide polymers via supramolecular interactions. Owing to the incredible catalytic efficiency and unique substrate selectivity, enzymes arouse considerable attention. To rival natural enzymes, various artificial enzymes have been developed over the last decades. Since supramolecular interactions play important roles in both substrate recognition and the process of enzymatic catalysis, designing artificial enzymes using supramolecular strategies is undoubtedly significant...
March 5, 2018: Current Opinion in Structural Biology
Kritika Gupta, Raghavan Varadarajan
Where convenient phenotypic readouts are available, saturation mutagenesis coupled to deep sequencing provides a rapid and facile method to infer sequence determinants of protein structure, stability and function. We provide brief descriptions and currently available options for the various steps involved, and mention limitations of current implementations. We also highlight recent applications such as estimating relative stabilities and affinities of protein variants, mapping epitopes, protein model discrimination and prediction of mutant phenotypes...
March 2, 2018: Current Opinion in Structural Biology
Silvio Panettieri, Rein V Ulijn
This review details recent developments in the design of supramolecular materials with customizable properties that can be coordinated in space and time. We highlight examples where both kinetic and thermodynamic considerations are incorporated in design, to address three challenges: control of order/disorder in supramolecular assembly; formation of structures with distinct functional domains; formation of out-of-equilibrium structures with controlled lifetimes. The examples that are discussed are based on self-assembling peptide and saccharide-based amphiphiles...
February 26, 2018: Current Opinion in Structural Biology
Adrià Pérez, Gerard Martínez-Rosell, Gianni De Fabritiis
Classical molecular dynamics (MD) simulations will be able to reach sampling in the second timescale within five years, producing petabytes of simulation data at current force field accuracy. Notwithstanding this, MD will still be in the regime of low-throughput, high-latency predictions with average accuracy. We envisage that machine learning (ML) will be able to solve both the accuracy and time-to-prediction problem by learning predictive models using expensive simulation data. The synergies between classical, quantum simulations and ML methods, such as artificial neural networks, have the potential to drastically reshape the way we make predictions in computational structural biology and drug discovery...
February 21, 2018: Current Opinion in Structural Biology
Paul S Nerenberg, Teresa Head-Gordon
Biomolecular force field development has been instrumental in improving the predictive power of molecular simulations over the past four decades. More recently, the era of large quantitative experimental datasets and ubiquitous high performance computing power has enabled rapid progress in the field. In this review we summarize recent developments in all-atom protein, nucleic acid, and small molecule force fields, paying specific attention to developments in parameterization methods and improvements in the representations of nonbonded interactions that are critical for solving the challenging biophysical problems of the present...
February 21, 2018: Current Opinion in Structural Biology
Trey A Ronnebaum, Audrey L Lamb
Microbes synthesize small, iron-chelating molecules known as siderophores to acquire iron from the environment. One way siderophores are generated is by nonribosomal peptide synthetases (NRPSs). The bioactive peptides generated by NRPS enzymes have unique chemical features, which are incorporated by accessory and tailoring domains or proteins. The first part of this review summarizes recent progress in NRPS structural biology. The second part uses the biosynthesis of pyochelin, a siderophore from Pseudomonas aeruginosa, as a case study to examine enzymatic methods for generating the observed diversity in NRPS-derived natural products...
February 15, 2018: Current Opinion in Structural Biology
Michael E Wall, Alexander M Wolff, James S Fraser
X-ray crystallography is experiencing a renaissance as a method for probing the protein conformational ensemble. The inherent limitations of Bragg analysis, however, which only reveals the mean structure, have given way to a surge in interest in diffuse scattering, which is caused by structure variations. Diffuse scattering is present in all macromolecular crystallography experiments. Recent studies are shedding light on the origins of diffuse scattering in protein crystallography, and provide clues for leveraging diffuse scattering to model protein motions with atomic detail...
February 15, 2018: Current Opinion in Structural Biology
Lucy J Colwell
Data driven computational approaches to predicting protein-ligand binding are currently achieving unprecedented levels of accuracy on held-out test datasets. Up until now, however, this has not led to corresponding breakthroughs in our ability to design novel ligands for protein targets of interest. This review summarizes the current state of the art in this field, emphasizing the recent development of deep neural networks for predicting protein-ligand binding. We explain the major technical challenges that have caused difficulty with predicting novel ligands, including the problems of sampling noise and the challenge of using benchmark datasets that are sufficiently unbiased that they allow the model to extrapolate to new regimes...
February 13, 2018: Current Opinion in Structural Biology
Shukun Luo, Liang Tong
The cysteine protease separase opens the cohesin ring by cleaving its kleisin subunit and is a pivotal cell cycle factor for the transition from metaphase to anaphase. It is inhibited by forming a complex with the chaperone securin, and in vertebrates, also by the Cdk1-cyclin B1 complex. Separase is activated upon the destruction of securin or cyclin B1 by the proteasome, after ubiquitination by the anaphase-promoting complex/cyclosome (APC/C). Here we review recent structures of the active protease segment of Chaetomium thermophilum separase in complex with a substrate-mimic inhibitor and full-length Saccharomyces cerevisiae and Caenorhabditis elegans separase in complex with securin...
February 13, 2018: Current Opinion in Structural Biology
Janice M Reimer, Asfarul S Haque, Michael J Tarry, T Martin Schmeing
Nonribosomal peptide synthetases (NRPSs) produce peptide products with wide-ranging biological activities. NRPSs are macromolecular machines with modular assembly-line logic, a complex catalytic cycle, moving parts and multiple active sites. They are organized into repeating sets of domains, called modules. Each module contains all functionality to introduce a building block into the growing peptide, many also perform cosynthetic tailoring. Structures of individual domains have provided insights into their catalytic mechanisms, but with one exception, larger NRPS proteins were refractory to structure determination...
February 11, 2018: Current Opinion in Structural Biology
Ajeet K Sharma, Edward P O'Brien
Protein folding research has been dominated by the assumption that thermodynamics determines protein structure and function. And that when the folding process is compromised in vivo the proteostasis machinery-chaperones, deaggregases, the proteasome-work to restore proteins to their soluble, functional form or degrade them to maintain the cellular pool of proteins in a quasi-equilibrium state. During the past decade, however, more and more proteins have been identified for which altering only their speed of synthesis alters their structure and function, the efficiency of the down-stream processes they take part in, and cellular phenotype...
February 2, 2018: Current Opinion in Structural Biology
Ilona Christy Unarta, Lizhe Zhu, Carmen Ka Man Tse, Peter Pak-Hang Cheung, Jin Yu, Xuhui Huang
Transcription elongation cycle (TEC) of RNA polymerase II (Pol II) is a process of adding a nucleoside triphosphate to the growing messenger RNA chain. Due to the long timescale events in Pol II TEC, an advanced computational technique, such as Markov State Model (MSM), is needed to provide atomistic mechanism and reaction rates. The combination of MSM and experimental results can be used to build a kinetic network model (KNM) of the whole TEC. This review provides a brief protocol to build MSM and KNM of the whole TEC, along with the latest findings of MSM and other computational studies of Pol II TEC...
February 2, 2018: Current Opinion in Structural Biology
Lena Kjellén, Ulf Lindahl
Glycosaminoglycans (GAGs) interact with a variety of proteins with important functions in development and homeostasis. Most of these proteins bind to heparin in vitro, a highly sulfated GAG species, although heparan sulfate and/or chondroitin/dermatan sulfate are more frequent physiological ligands. Binding affinity and specificity are determined by charge distribution, mainly due to sulfate and carboxylate groups and by GAG chain conformation. Interactions may be nonspecific, essentially reflecting charge density or highly specific, dependent on rare GAG-structural features...
February 1, 2018: Current Opinion in Structural Biology
Van Son Nguyen, Badreddine Douzi, Eric Durand, Alain Roussel, Eric Cascales, Christian Cambillau
The Type VI secretion system (T6SS) is a dynamic nanomachine present in many Gram-negative bacteria. Using a contraction mechanism similar to that of myophages, bacteriocins or anti-feeding prophages, it injects toxic effectors into both eukaryotic and prokaryotic cells. T6SS assembles three large ensembles: the trans-membrane complex (TMC), the baseplate and the tail. Recently, the tail structure has been elucidated by cryo electron microscopy (cryoEM) in extended and contracted forms. The structure of the trans-membrane complex has been deciphered using a combination of X-ray crystallography and EM...
February 1, 2018: Current Opinion in Structural Biology
Jonas Barandun, Mirjam Hunziker, Sebastian Klinge
The small subunit processome is the first precursor of the small eukaryotic ribosomal subunit. During its assembly in the nucleolus, many ribosome biogenesis factors, an RNA chaperone, and ribosomal proteins associate with the nascent pre-rRNA. Biochemical studies have elucidated the rRNA-subdomain dependent recruitment of these factors during SSU processome assembly and have been complemented by structural studies of the assembled particle. Ribosome biogenesis factors encapsulate and guide subdomains of pre-ribosomal RNA in distinct compartments...
January 31, 2018: Current Opinion in Structural Biology
Eliot Boulanger, Jeremy N Harvey
Hybrid computational methods describing a small region of a biomolecular system with quantum mechanics and the bulk with molecular mechanics, referred to as QM/MM methods, are now a central part of computational biochemistry. This review considers developments in the QM/MM approach that make it easier to calculate free energies using accurate QM-based potential energy expressions. We also describe techniques to treat electronic coupling between the core region and the MM environment. Polarizability of the protein matrix is important but so is electronic coupling...
January 30, 2018: Current Opinion in Structural Biology
Vojtěch Mlýnský, Giovanni Bussi
RNA function is intimately related to its structural dynamics. Molecular dynamics simulations are useful for exploring biomolecular flexibility but are severely limited by the accessible timescale. Enhanced sampling methods allow this timescale to be effectively extended in order to probe biologically relevant conformational changes and chemical reactions. Here, we review the role of enhanced sampling techniques in the study of RNA systems. We discuss the challenges and promises associated with the application of these methods to force-field validation, exploration of conformational landscapes and ion/ligand-RNA interactions, as well as catalytic pathways...
January 29, 2018: Current Opinion in Structural Biology
Kristoffer E Johansson, Kresten Lindorff-Larsen
Recent years have witnessed substantial progress in our ability to design proteins with specific structures and to introduce new functionalities into existing protein scaffolds. Such protein design efforts test our understanding of the biophysical and functional mechanisms of naturally evolved proteins. At the same time, we also know that proteins are dynamical entities, and that many proteins rely on detailed dynamical mechanisms for regulation and function. Thus, the success of design methods, especially in relation to functional proteins, might benefit from explicit considerations of conformational heterogeneity and dynamics...
January 29, 2018: Current Opinion in Structural Biology
Hans Adrian Bunzel, Xavier Garrabou, Moritz Pott, Donald Hilvert
Exploring the sequence space of enzyme catalysts is ultimately a numbers game. Ultrahigh-throughput screening methods for rapid analysis of millions of variants are therefore increasingly important for investigating sequence-function relationships, searching large metagenomic libraries for interesting activities, and accelerating enzyme evolution in the laboratory. Recent applications of such technologies are reviewed here, with a particular focus on the practical benefits of droplet-based microfluidics for the directed evolution of natural and artificial enzymes...
January 29, 2018: Current Opinion in Structural Biology
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