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Current Opinion in Structural Biology

Rinku Jain, Aneel K Aggarwal, Olga Rechkoblit
The eukaryotic DNA replication machinery is conserved from yeast to humans and requires the actions of multiple DNA polymerases. In addition to replicative DNA polymerases for duplication of the leading and lagging DNA strands, another group of specialized polymerases is required for DNA repair and/or translesion DNA synthesis (TLS). We emphasize here recent findings that accelerate our understanding of the structure and mechanisms of these remarkable enzymes. We also highlight growing evidence on the role of DNA polymerases in the origin of certain cancers, and paradoxically as emerging targets for cancer therapy...
July 10, 2018: Current Opinion in Structural Biology
Isabelle Compagnon, Baptiste Schindler, Gina Renois-Predelus, Régis Daniel
Glycosaminoglycans are biopolymers present in mammalian cells or in the extracellular matrix. To address their structure, the nature of the hexuronic acids and the position of sulfate groups must be determined. Tandem mass spectrometry using collision induced dissociation or electron-based fragmentation techniques, is a well-established approach for the identification of glycans but suffers from the frequent lack of diagnostic fragments in the case of glycosaminoglycans. This review presents alternative fragmentation techniques, namely photofragmentation in the IR and the UV ranges...
July 10, 2018: Current Opinion in Structural Biology
Kaoru Sato, Mikiko C Siomi
Transposons occupy a large proportion of eukaryotic genomes. Spontaneous movement of transposons within the genome leads to genomic mutations that are often life threatening. To avoid such outcomes, host species have acquired an elaborate molecular pathway during evolution, in which PIWI proteins and PIWI-interacting RNAs (piRNAs) collaboratively control transposons to maintain germline genome integrity. Studies of PIWI-piRNA-based transposon silencing have uncovered the molecular mechanisms underlying piRNA biogenesis and the silencing mode-of-action in the pathway...
July 7, 2018: Current Opinion in Structural Biology
Patrick J Almhjell, Jeremy H Mills
The ability to rationally design metalloproteins with desired functions remains a difficult challenge despite many years of effort. Recently, the potential of using genetically encoded metal-chelating non-canonical amino acids (NCAAs) to circumvent longstanding difficulties in this field has begun to be explored. In this review, we describe the development of this approach and its application to the rational design or directed evolution of NCAA-containing metalloproteins in which the bound metal ions serve in structural roles, as catalysts, or as regulators of the assembly or disassembly of protein complexes...
July 3, 2018: Current Opinion in Structural Biology
Fabian Sesterhenn, Jaume Bonet, Bruno E Correia
Vaccines have been one of the most successful interventions in global health. However, traditional vaccine development has proven insufficient to deal with pathogens that elude the immune system through highly variable and non-functional epitopes. Emerging B cell technologies have yielded potent monoclonal antibodies targeting conserved epitopes, and their structural characterization has provided templates for rational immunogen design. Here, we review immunogen design strategies that leverage structural information to steer bulk immune responses towards the induction of precise antibody specificities targeting key antigenic sites...
June 28, 2018: Current Opinion in Structural Biology
Andrew J Fisher, Peter A Beal
All messenger RNAs in eukaryotes are modified co-transcriptionally and post-transcriptionally. They are all capped at the 5'-end and polyadenylated at the 3'-end. However, many mRNAs are also found to be chemically modified internally for regulation of mRNA processing, translation, stability, and to recode the message. This review will briefly summarize the structural basis for formation of the two most common modifications found at internal sites in mRNAs; methylation and deamination. The structures of the enzymes that catalyze these modifications show structural similarity to other family members within each modifying enzyme class...
June 15, 2018: Current Opinion in Structural Biology
Nathanael A Caveney, Franco Kk Li, Natalie Cj Strynadka
The bacterial cell wall is a complex polymeric structure with essential roles in defence, survival and pathogenesis. Common to both Gram-positive and Gram-negative bacteria is the mesh-like peptidoglycan sacculus that surrounds the outer leaflet of the cytoplasmic membrane. Recent crystallographic studies of enzymes that comprise the peptidoglycan biosynthetic pathway have led to significant new understanding of all stages. These include initial multi-step cytosolic formation of sugar-pentapeptide precursors, transfer of the precursors to activated polyprenyl lipids at the membrane inner leaflet and flippase mediated relocalization of the resulting lipid II precursors to the outer leaflet where glycopolymerization and subsequent peptide crosslinking are finalized...
June 6, 2018: Current Opinion in Structural Biology
Kristin E Low, P Lynne Howell
Bacteria predominantly exist as matrix embedded communities of cells called biofilms. The biofilm matrix is made up of a variety of self-produced extracellular components including DNA, proteins, and exopolysaccharides. Bacterial exopolysaccharides have been implicated in surface adhesion, resistance to antibiotics, and protection from host immune systems. Herein we review the structure and function of the proteins involved in the production of the Gram-negative synthase-dependent exopolysaccharides: alginate, poly-β(1,6)-N-acetyl-d-glucosamine (PNAG), cellulose, and the Pel polysaccharide...
May 26, 2018: Current Opinion in Structural Biology
Sharon Fischman, Yanay Ofran
Antibody design aims to create new antibodies with biological activity that can be used in therapy and research. Traditional methods for antibody discovery, such as animal immunization and large-scale library screening, generate antibodies that bind to the target of interest, but do not necessarily have the desired functional effect. Computational methods can be utilized as a means to guide the search for biologically relevant antibodies, focusing on specificity and affinity determinants to target a particular region of the antigen...
May 19, 2018: Current Opinion in Structural Biology
Katie J Grayson, Jl Ross Anderson
Though established 40 years ago, the field of de novo protein design has recently come of age, with new designs exhibiting an unprecedented level of sophistication in structure and function. With respect to catalysis, de novo enzymes promise to revolutionise the industrial production of useful chemicals and materials, while providing new biomolecules as plug-and-play components in the metabolic pathways of living cells. To this end, there are now de novo metalloenzymes that are assembled in vivo, including the recently reported C45 maquette, which can catalyse a variety of substrate oxidations with efficiencies rivalling those of closely related natural enzymes...
May 10, 2018: Current Opinion in Structural Biology
Takamitsu Hattori, Shohei Koide
Despite increasing demands for antibodies to post-translational modifications (PTMs), fundamental difficulties in molecular recognition of PTMs hinder the generation of highly functional anti-PTM antibodies using conventional methods. Recently, advanced approaches in protein engineering and design that have been established for biologics development were applied to successfully generating highly functional anti-PTM antibodies. Furthermore, structural analyses of anti-PTM antibodies revealed unprecedented binding modes that substantially increased the antigen-binding surface...
May 9, 2018: Current Opinion in Structural Biology
Moon-Hyeong Seo, Philip M Kim
Protein-protein interactions (PPIs) are essential to governing virtually all cellular processes. Of particular importance are the versatile motif-mediated interactions (MMIs), which are thus far underrepresented in available interaction data. This is largely due to technical difficulties inherent in the properties of MMIs, but due to the increasing recognition of the vital roles of MMIs in biology, several systematic approaches have recently been developed to detect novel MMIs. Consequently, rapidly growing numbers of motifs are being identified and pursued further for therapeutic applications...
May 3, 2018: Current Opinion in Structural Biology
Chen Liang, Ming-Chien Hsieh, Noel X Li, David G Lynn
The morphological diversity of amyloid assemblies has complicated the development of disease therapies and the design of novel biomaterials for decades. Here we review the conformational evolution of amyloids from the initial liquid-liquid phase separation into the oligomeric particle phase to the nucleation of the more ordered assembly phases. With mounting evidence that the assemblies emerging from the oligomeric phases may not be stable in solution and undergo further structural transitions, we propose the concept of conformational evolution, where mutations may occur at the ends or on the surface of the pre-existing fibers and different morphologies are under selection throughout the assembly process...
May 2, 2018: Current Opinion in Structural Biology
Ding Xu, Katelyn Arnold, Jian Liu
Heparan sulfate (HS) is widely present on the animal cell surface and in the extracellular matrix. HS achieves its biological functions by interacting with proteins to change proteins' conformation, oligomerization state and cellular location. The challenging question to study HS is how to dissect the relationship between the structures of HS and the biological activities. In the past several years, crucial techniques have been developed to overcome this challenge. A novel chemoenzymatic method to synthesize structurally defined HS oligosaccharides has offered a key access to this class of sulfated carbohydrate molecules...
April 20, 2018: Current Opinion in Structural Biology
Mahmoud L Nasr, Gerhard Wagner
Covalently circularized nanodiscs (cNDs) represent a significant advance in the durability and applicability of nanodisc technology. The new cNDs demonstrate higher size homogeneity and improved stability compared with that of non-circularized forms. Moreover, cNDs can be prepared at various defined sizes up to 80-nm diameter. The large cNDs can house much larger membrane proteins and their complexes than was previously possible with the conventional nanodiscs. In order to experience the full advantages of covalent circularization, high quality circularized scaffold protein and nanodisc samples are needed...
April 17, 2018: Current Opinion in Structural Biology
Valeria A Risso, Jose M Sanchez-Ruiz, S Banu Ozkan
Approximations to the sequences of ancestral proteins can be derived from the sequences of their modern descendants. Proteins encoded by such reconstructed sequences can be prepared in the laboratory and subjected to experimental scrutiny. These 'resurrected' ancestral proteins often display remarkable properties, reflecting ancestral adaptations to intra-cellular and extra-cellular environments that differed from the environments hosting modern/extant proteins. Recent experimental and computational work has specifically discussed high stability, substrate and catalytic promiscuity, conformational flexibility/diversity and altered patterns of interaction with other sub-cellular components...
April 13, 2018: Current Opinion in Structural Biology
Jérôme Loc'h, Marc Delarue
Terminal deoxynucleotidyltransferase (TdT) is a member of the polX family which is involved in DNA repair. It has been known for years as an untemplated DNA polymerase used during V(D)J recombination to generate diversity at the CDR3 region of immunoglobulins and T-cell receptors. Recently, however, TdT was crystallized in the presence of a complete DNA synapsis made of two double-stranded DNA (dsDNA), each with a 3' protruding end, and overlapping with only one micro-homology base-pair, thus giving structural insight for the first time into DNA synthesis across strands...
April 12, 2018: Current Opinion in Structural Biology
Michael K Fenwick, Steven E Ealick
Approximately 2000 structures of methyltransferases (MTases) are currently available, displaying fifteen different folds for binding a methyl donor and providing molecular level insight into nearly half the human methyltransferome. Several MTases involved in gene expression and regulation are catalytically inefficient when isolated, and their catalytic domains often show inhibitory active site architectures. Recently reported structures of complexes that more closely reflect biological context have begun to reveal the structural basis of activation...
April 11, 2018: Current Opinion in Structural Biology
Christoph Thomas, Robert Tampé
ATP-binding cassette (ABC) transporters are found in all domains of life and constitute one of the largest protein superfamilies. ABC transporters harness the energy of ATP binding and hydrolysis to shuttle a diverse range of substrates across cell membranes. While higher-resolution structures of ABC transporters have so far exclusively been obtained by X-ray crystallography, recent advances in single-particle cryogenic electron microscopy (cryo-EM) have provided a deluge of exciting new structures of medically relevant bacterial and human ABC proteins, including those of the cystic fibrosis transmembrane conductance regulator (CFTR), and of supramolecular assemblies involving ABC transporters, like the ATP-sensitive potassium (KATP ) channel and the peptide-loading complex (PLC), which is crucially involved in the presentation of antigens in adaptive immunity...
April 7, 2018: Current Opinion in Structural Biology
Timm Maier, Kira J Weissman
No abstract text is available yet for this article.
April 2018: Current Opinion in Structural Biology
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