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Current Opinion in Structural Biology

Fei Ye, Menglong Zeng, Mingjie Zhang
Membrane-associated guanylate kinases (MAGUKs) are a family of scaffold proteins that are enriched in cellular junctions and essential for tissue development and homeostasis. Mutations of MAGUKs are linked to many human diseases including cancers, psychiatric disorders, and intellectual disabilities. MAGUKs share a common PDZ-SH3-GK tandem domain organization at the C-terminal end. In this review, we summarize the mechanistic basis governing target recognition and regulations of this binding by the PDZ-SH3-GK tandem of various MAGUKs...
September 13, 2017: Current Opinion in Structural Biology
Henry N Chapman, Petra Fromme
Bright and coherent X-ray sources, such free-electron lasers, have spurred large activities in developing new methods to obtain the structures of biological macromolecules. In particular, single-molecule diffraction is highly desired, as it would abolish the need for crystallization. It provides considerably more diffraction intensity information than needed to solve a structure, unlike crystal diffraction, which is usually insufficient for direct phasing. To overcome the challenge of weak scattering signals of single molecules, the direct phasing approaches in coherent diffractive imaging have been combined with crystals in several imaginative ways...
September 13, 2017: Current Opinion in Structural Biology
Lindsay A Baker, Michael Grange, Kay Grünewald
Transmission electron microscopy has a long history in cellular biology. Fixed and stained samples have been used for cellular imaging for over 50 years, but suffer from sample preparation induced artifacts. Electron cryo-tomography (cryoET) instead uses frozen-hydrated samples, without chemical modification, to determine the structure of macromolecular complexes in their native environment. Recent developments in electron microscopes and associated technologies have greatly expanded our ability to visualize cellular features and determine the structures of macromolecular complexes in situ...
September 12, 2017: Current Opinion in Structural Biology
Jonathan D Tyzack, Nicholas Furnham, Ian Sillitoe, Christine M Orengo, Janet M Thornton
In this review, we will explore recent computational approaches to understand enzyme evolution from the perspective of protein structure, dynamics and promiscuity. We will present quantitative methods to measure the size of evolutionary steps within a structural domain, allowing the correlation between change in substrate and domain structure to be assessed, and giving insights into the evolvability of different domains in terms of the number, types and sizes of evolutionary steps observed. These approaches will help to understand the evolution of new catalytic and non-catalytic functionality in response to environmental demands, showing potential to guide de novoenzyme design and directed evolution experiments...
September 7, 2017: Current Opinion in Structural Biology
Sjors Hw Scheres, Kiyoshi Nagai
The spliceosome is an intricate molecular machine which catalyses the removal of introns from eukaryotic mRNA precursors by two trans-esterification reactions (branching and exon ligation) to produce mature mRNA with uninterrupted protein coding sequences. The structures of the spliceosome in several key states determined by electron cryo-microscopy have greatly advanced our understanding of its molecular mechanism. The catalytic RNA core is formed during the activation of the fully assembled B to Bact complex and remains largely unchanged throughout the splicing cycle...
September 6, 2017: Current Opinion in Structural Biology
Martin Caffrey, David Drew
No abstract text is available yet for this article.
August 31, 2017: Current Opinion in Structural Biology
George P Lisi, J Patrick Loria
Modern interpretations of allostery typically rely on conformational ensembles to describe enzyme function. Conformational motions controlling these ensembles are often stimulated or quenched by allosteric effectors, and are critical to optimizing ligand binding pockets and enzyme architectures. Thus, enzymes rely on dynamic allosteric pathways that transmit long-range binding information to control catalysis. In this review, we provide a brief discussion of the ever-expanding principles of allosteric regulation in enzyme catalysis and highlight in-depth studies of three enzymes that have contributed to the paradigms of dynamic allostery...
August 30, 2017: Current Opinion in Structural Biology
Ottilie von Loeffelholz, S Kundhavai Natchiar, Nadia Djabeur, Alexander G Myasnikov, Hanna Kratzat, Jean-François Ménétret, Isabelle Hazemann, Bruno P Klaholz
Cryo electron microscopy (cryo-EM) historically has had a strong impact on the structural and mechanistic analysis of protein synthesis by the prokaryotic and eukaryotic ribosomes. Vice versa, studying ribosomes has helped moving forwards many methodological aspects in single particle cryo-EM, at the level of automated data collection and image processing including advanced techniques for particle sorting to address structural and compositional heterogeneity. Here we review some of the latest ribosome structures, where cryo-EM allowed gaining unprecedented insights based on 3D structure sorting with focused classification and refinement methods helping to reach local resolution levels better than 3Å...
August 26, 2017: Current Opinion in Structural Biology
Mohammad A Siddiq, Georg Ka Hochberg, Joseph W Thornton
Specific interactions between proteins and their molecular partners drive most biological processes, so understanding how these interactions evolve is an important question for biochemists and evolutionary biologists alike. It is often thought that ancestral proteins were systematically more promiscuous than modern proteins and that specificity usually evolves after gene duplication by partitioning and refining the activities of multifunctional ancestors. However, recent studies using ancestral protein reconstruction (APR) have found that ligand-specific functions in some modern protein families evolved de novo from ancestors that did not already have those functions...
August 22, 2017: Current Opinion in Structural Biology
Bryan J Leong, Robert L Last
Specialized metabolic enzymes and metabolite diversity evolve through a variety of mechanisms including promiscuity, changes in substrate specificity, modifications of gene expression and gene duplication. For example, gene duplication and substrate binding site changes led to the evolution of the glucosinolate biosynthetic enzyme, AtIPMDH1, from a Leu biosynthetic enzyme. BAHD acyltransferases illustrate how enzymatic promiscuity leads to metabolite diversity. The examples 4-coumarate:CoA ligase and aromatic acid methyltransferases illustrate how promiscuity can potentiate the evolution of these specialized metabolic enzymes...
August 16, 2017: Current Opinion in Structural Biology
Wah Chiu, Kenneth H Downing
No abstract text is available yet for this article.
August 8, 2017: Current Opinion in Structural Biology
Wen Jiang, Liang Tang
During the development of single particle cryo-EM in past five decades, icosahedral viruses have led the resolution progress owing to their large mass and high symmetry. Many technical advances in cryo-EM were first established with viruses. Since reaching ∼4Å resolution in 2008, it has become a relatively routine task to solve the atomic structure of isolated viruses. The future of structural virology will be increasingly focused on remaining challenges including solving structures of jumbo viruses, intermediate functional states during assembly, maturation, and infection, and in situ structures...
August 5, 2017: Current Opinion in Structural Biology
James M Murphy, Peter D Mace, Patrick A Eyers
Pseudoenzymes were first described more than 50 years ago, when it was recognised that a subset of proteins that are structurally homologous to active enzymes lack amino acids necessary for catalytic activity. Recently, interest in pseudoenzymes has surged as it has become apparent that they constitute ∼10% of proteomes and perform essential metabolic and signalling functions that can be experimentally distinguished from catalytic outputs of enzymes. Here, we highlight recent structural studies of pseudoenzymes, which have revealed the molecular basis for roles as allosteric regulators of conventional enzymes, as molecular switches and integrators, as hubs for assembling protein complexes, and as competitors of substrate availability and holoenzyme assembly...
August 5, 2017: Current Opinion in Structural Biology
Heena Khatter, Matthias K Vorländer, Christoph W Müller
The majority of non-protein-coding RNAs present in eukaryotic cells comprises rRNAs, tRNAs and U6 snRNA that are involved in protein biosynthesis and are synthesized by DNA-dependent-RNA polymerase I and III. The transcription cycle (initiation, elongation and termination) has similar principles in all three nuclear RNA polymerases with specific features that are reflected back in their structures. Recently, owing to the 'resolution revolution' in electron cryo-microscopy, there has been a significant advancement in the understanding of these molecular machines...
July 22, 2017: Current Opinion in Structural Biology
Jürgen M Plitzko, Benjamin Schuler, Philipp Selenko
Recent developments in cellular cryo-electron tomography, in-cell single-molecule Förster resonance energy transfer-spectroscopy, nuclear magnetic resonance-spectroscopy and electron paramagnetic resonance-spectroscopy delivered unprecedented insights into the inner workings of cells. Here, we review complementary aspects of these methods and provide an outlook toward joint applications in the future.
July 20, 2017: Current Opinion in Structural Biology
Agnel Praveen Joseph, Guido Polles, Frank Alber, Maya Topf
A wide variety of experimental techniques can be used for understanding the precise molecular mechanisms underlying the activities of cellular assemblies. The inherent limitations of a single experimental technique often requires integration of data from complementary approaches to gain sufficient insights into the assembly structure and function. Here, we review popular computational approaches for integrative modelling of cellular assemblies, including protein complexes and genomic assemblies. We provide recent examples of integrative models generated for such assemblies by different experimental techniques, especially including data from 3D electron microscopy (3D-EM) and chromosome conformation capture experiments, respectively...
July 20, 2017: Current Opinion in Structural Biology
Scott Horowitz, Philipp Koldewey, Frederick Stull, James Ca Bardwell
Chaperones are important in preventing protein aggregation and aiding protein folding. How chaperones aid protein folding remains a key question in understanding their mechanism. The possibility of proteins folding while bound to chaperones was reintroduced recently with the chaperone Spy, many years after the phenomenon was first reported with the chaperones GroEL and SecB. In this review, we discuss the salient features of folding while bound in the cases for which it has been observed and speculate about its biological importance and possible occurrence in other chaperones...
July 19, 2017: Current Opinion in Structural Biology
Yaqiang Wang, Juli Feigon
Telomerase is an RNP that synthesizes the 3' ends of linear chromosomes and is an important regulator of telomere length. It contains a single long non-coding telomerase RNA (TER), telomerase reverse transcriptase (TERT), and other proteins that vary among organisms. Recent progress in structural biology of telomerase includes reports of the first cryo-electron microscopy structure of telomerase, from Tetrahymena, new crystal structures of TERT domains, telomerase RNA structures and models, and identification in Tetrahymena telomerase holoenzyme of human homologues of telomere-associated proteins that have provided a more unified view of telomerase interaction at telomeres as well as insights into the role of telomerase RNA in activity and assembly...
July 18, 2017: Current Opinion in Structural Biology
Matthew K Higgins, Susan M Lea
While protein crystallography has, for many years, been the most used method for structural analysis of macromolecular complexes, remarkable recent advances in high-resolution electron cryo-microscopy led to suggestions that 'the revolution will not be crystallised'. Here we highlight the current success rate, speed and ease of modern crystallographic structure determination and some recent triumphs of both 'classical' crystallography and the use of X-ray free electron lasers. We also outline fundamental differences between structure determination using X-ray crystallography and electron microscopy...
July 4, 2017: Current Opinion in Structural Biology
Ye Ji, Yohanna Jb White, Jodi A Hadden, Oliver C Grant, Robert J Woods
Understanding the molecular origin of influenza receptor specificity is complicated by the paucity of quantitative affinity measurements, and the qualitative and variable nature of glycan array data. Further obstacles arise from the varied impact of viral glycosylation and the relatively narrow spectrum of biologically relevant receptors present on glycan arrays. A survey of receptor conformational properties is presented, leading to the conclusion that conformational entropy plays a key role in defining specificity, as does the newly reported ability of biantennary receptors that terminate in Siaα2-6Gal sequences to form bidentate interactions to two binding sites in a hemagglutinin trimer...
July 1, 2017: Current Opinion in Structural Biology
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