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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
Stefan Imseng, Christopher Hs Aylett, Timm Maier
The phosphatidylinositol 3-kinase related protein kinases (PIKKs) are key to the regulation of a variety of eukaryotic cellular processes including DNA repair and growth regulation. While these massive proteins had long resisted structural analysis, recent advances in electron cryo-microscopy have now facilitated structural analysis of the major examples of PIKKs, including mTOR, DNA-PK, ATM, ATR and TRAPP/Tra1. In these PIKKs, the carboxy-terminal kinase domains and their proximal regions are structurally conserved...
April 3, 2018: Current Opinion in Structural Biology
Christian Sieben, Kyle M Douglass, Paul Guichard, Suliana Manley
Super-resolution fluorescence microscopy (SRM) is increasingly being applied as a complementary method to resolve the organization of large biomolecular assemblies. One of its main advantages is that it provides information on protein organization and identity simultaneously, within the native cellular milieu. It also extends the accessible range of structures up to the micrometer scale, offering complementary information relative to classical structural biology methods. Furthermore, SRM is capable of resolving the organization of some biomolecular assemblies not accessible to other methods...
April 2, 2018: Current Opinion in Structural Biology
Mijo Simunovic, Patricia Bassereau, Gregory A Voth
Lipid membranes play key roles in cells, such as in trafficking, division, infection, remodeling of organelles, among others. The key step in all these processes is creating membrane curvature, typically under the control of many anchored, adhered or included proteins. However, it has become clear that the membrane itself can mediate the interactions among proteins to produce highly ordered assemblies. Computer simulations are ideally suited to investigate protein organization and the dynamics of membrane remodeling at near-micron scales, something that is extremely challenging to tackle experimentally...
March 30, 2018: Current Opinion in Structural Biology
Julio F Cordero-Morales, Valeria Vásquez
Membrane lipid composition and remodeling influence the function of ion channels. Polyunsaturated fatty acids (PUFAs) and their derivatives modulate ion channel function; whether this effect occurs directly by binding to the protein or indirectly through alteration of membranes' mechanical properties has been difficult to distinguish. There are a large number of studies addressing the effect of fatty acids; recent structural and functional analyses have identified binding sites and provided further evidence for the role of the plasma membrane in ion channel function...
March 27, 2018: Current Opinion in Structural Biology
Pedro Bule, Virgínia Mr Pires, Carlos Mga Fontes, Victor D Alves
Cohesin-Dockerin interactions are at the core of cellulosomal assembly and organization. They are highly specific and form stable complexes, allowing cellulosomes to adopt distinct conformations. Each cellulosomal system seems to have a particular organizational strategy that can vary in complexity according to the nature of its Cohesin-Dockerin interactions. Hence, several efforts have been undertaken to reveal the mechanisms that govern the specificity, affinity and flexibility of these protein-protein interactions...
March 26, 2018: Current Opinion in Structural Biology
Charles R Sanders, James M Hutchison
Spectacular recent progress in structural biology has led to determination of the structures of many integral membrane enzymes that catalyze reactions in which at least one substrate also is membrane bound. A pattern of results seems to be emerging in which the active site chemistry of these enzymes is usually found to be analogous to what is observed for water soluble enzymes catalyzing the same reaction types. However, in light of the chemical, structural, and physical complexity of cellular membranes plus the presence of transmembrane gradients and potentials, these enzymes may be subject to membrane-specific regulatory mechanisms that are only now beginning to be uncovered...
March 26, 2018: Current Opinion in Structural Biology
Yogesh Hooda, Trevor F Moraes
The surface of many Gram-negative bacteria contains lipidated protein molecules referred to as surface lipoproteins or SLPs. SLPs play critical roles in host immune evasion, nutrient acquisition and regulation of bacterial stress response, and have been extensively studied as vaccine antigens. The aim of this review is to summarize the recent studies that have investigated the biosynthetic and translocation pathways used by different bacterial species to deliver SLPs to the surface. We will specifically focus on Slam, a novel outer membrane protein first discovered in pathogenic Neisseria sp...
March 23, 2018: Current Opinion in Structural Biology
Dorothy D Majewski, Liam J Worrall, Natalie Cj Strynadka
The acquisition and evolution of customized and often highly complex secretion systems allows Gram-negative bacteria to efficiently passage large macromolecules across both inner and outer membranes and, in some cases, that of the infected host. Essential to the virulence and ultimate survival of the many pathogenic species that encode them, secretion systems export a wide variety of effector proteins and DNA as well as the downstream extracellular filaments of the secretion apparatus themselves. Although these customized secretion systems differ in their cytosolic and inner membrane components, several commonly rely on the secretin family of giant pores to allow these large substrates to traverse the outer membrane...
March 23, 2018: Current Opinion in Structural Biology
Robert A Townley, Hannes E Bülow
Glycosaminoglycans (GAGs) such as heparan sulfate, chondroitin/dermatan sulfate, and keratan sulfate are linear glycans, which when attached to protein backbones form proteoglycans. GAGs are essential components of the extracellular space in metazoans. Extensive modifications of the glycans such as sulfation, deacetylation and epimerization create structural GAG motifs. These motifs regulate protein-protein interactions and are thereby repsonsible for many of the essential functions of GAGs. This review focusses on recent genetic approaches to characterize GAG motifs and their function in defined signaling pathways during development...
March 23, 2018: Current Opinion in Structural Biology
Pilar Cossio, Gerhard Hummer
Likelihood-based analysis of single-particle electron microscopy images has contributed much to the recent improvements in resolution. By treating particle orientations and classes probabilistically, uncertainties in the reconstruction process are explicitly accounted for, and the risk of bias towards the initial model is diminished. As a result, the quality and reliability of the reconstructions have greatly improved at manageable computational cost. Likelihood-based analysis of electron microscopy images also offers a route to direct coordinate refinement for dynamic systems, as an alternative to 3D density reconstruction...
March 23, 2018: Current Opinion in Structural Biology
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