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Current Opinion in Structural Biology

Surekha Nimma, Thomas Ve, Simon J Williams, Bostjan Kobe
TIR (Toll/interleukin-1 receptor/resistance protein) domains feature in animal, plant and bacterial proteins involved in innate immunity pathways and associated processes. They function through protein:protein interactions, in particular self-association and homotypic association with other TIR domains. Structures of TIR domains from all phyla have been determined, but common association modes have only emerged for plant and bacterial TIR domains, and not for mammalian TIR domains. Numerous attempts involving hybrid approaches, which have combined structural, computational, mutagenesis and biophysical data, have failed to converge onto common models of how these domains associate and function...
January 13, 2017: Current Opinion in Structural Biology
Slavica Jonić
Thanks to latest technical advances in cryo-electron microscopy (cryo-EM), structures of macromolecular complexes (viruses, ribosomes, etc.) are now often obtained at near-atomic resolution. Also, studies of conformational changes of complexes, in connection with their function, are gaining ground. Conformational variability analysis is usually done by classifying images in a number of discrete classes supposedly representing all conformational states present in the specimen. However, discrete classes cannot be meaningfully defined when the conformational change is continuous (the specimen contains a continuum of states instead of a few discrete states)...
January 11, 2017: Current Opinion in Structural Biology
Sneha Vishwanath, Anshul Sukhwal, Ramanathan Sowdhamini, Narayanaswamy Srinivasan
Remarkable features that are achieved in a protein-protein complex to precise levels are stability and specificity. Deviation from the normal levels of specificity and stability, which is often caused by mutations, could result in disease conditions. Chemical nature, 3-D arrangement and dynamics of interface residues code for both specificity and stability. This article reviews roles of interfacial residues in transient protein-protein complexes. It is proposed that aside from hotspot residues conferring stability to the complex, a small set of 'rigid' residues at the interface that maintain conformation between complexed and uncomplexed forms, play a major role in conferring specificity...
January 11, 2017: Current Opinion in Structural Biology
Igor N Berezovsky, Ugo Bastolla
No abstract text is available yet for this article.
January 10, 2017: Current Opinion in Structural Biology
Gustav Vaaje-Kolstad, Zarah Forsberg, Jennifer Sm Loose, Bastien Bissaro, Vincent Gh Eijsink
Lytic polysaccharide monooxygenases (LPMOs) catalyze the oxidative cleavage of glycosidic bonds and represent a promising resource for development of industrial enzyme cocktails for biomass processing. LPMOs show high sequence and modular diversity and are known, so far, to cleave insoluble substrates such as cellulose, chitin and starch, as well as hemicelluloses such as beta-glucan, xyloglucan and xylan. All LPMOs share a catalytic histidine brace motif to bind copper, but differ strongly when it comes to the nature and arrangement of residues on the substrate-binding surface...
January 10, 2017: Current Opinion in Structural Biology
Anna D Cunningham, Nir Qvit, Daria Mochly-Rosen
Protein-protein interactions are essential for almost all intracellular and extracellular biological processes. Regulation of protein-protein interactions is one strategy to regulate cell fate in a highly selective manner. Specifically, peptides are ideal candidates for inhibition of protein-protein interactions because they can mimic a protein surface to effectively compete for binding. Additionally, peptides are synthetically accessible and can be stabilized by chemical modifications. In this review, we survey screening and rational design methods for identifying peptides to inhibit protein-protein interactions, as well as methods for stabilizing peptides to effectively mimic protein surfaces...
January 4, 2017: Current Opinion in Structural Biology
Massimiliano Bonomi, Gabriella T Heller, Carlo Camilloni, Michele Vendruscolo
The biological functions of protein molecules are intimately dependent on their conformational dynamics. This aspect is particularly evident for disordered proteins, which constitute perhaps one-third of the human proteome. Therefore, structural ensembles often offer more useful representations of proteins than individual conformations. Here, we describe how the well-established principles of protein structure determination should be extended to the case of protein structural ensembles determination. These principles concern primarily how to deal with conformationally heterogeneous states, and with experimental measurements that are averaged over such states and affected by a variety of errors...
January 4, 2017: Current Opinion in Structural Biology
Philippe Cuniasse, Paulo Tavares, Elena V Orlova, Sophie Zinn-Justin
CryoEM is presently providing structures of biocomplexes considered intractable to analysis by other structural techniques. NMR is playing an important role in delivering structural information on dynamics events and conformational heterogeneity. Impressive results were obtained by combining cryoEM and either liquid- or solid-state NMR, revealing the structures of cellular machines, filaments and amyloid fibrils. NMR solution structures of proteins and nucleic acids were fitted, together with crystallographic structures, into cryoEM maps of large complexes, to decipher their assembly mechanisms and describe their functional dynamics...
January 2, 2017: Current Opinion in Structural Biology
Kristof Moonens, Han Remaut
Infectious disease processes like bacterial adherence or the activity of secreted toxins frequently gain host and tissue specificity by glycan binding interactions with the host glycome. Recent functional and structural studies highlight the high niche specialization of bacterial lectins, but also reveal a remarkable plasticity in their glycan binding sites and mechanisms, to adapt to host glycome dynamics or changing environmental conditions at the site of infection. In this review we put emphasis on new structural insights in host adaptation and dynamics of bacterial carbohydrate binding adhesins and toxins in human pathogens like uropathogenic and enteropathogenic Escherichia coli, Helicobacter pylori, Yersinia pestis or Vibrio cholera...
December 30, 2016: Current Opinion in Structural Biology
Fabrizio Pucci, Marianne Rooman
The molecular bases of thermal and cold stability and adaptation, which allow proteins to remain folded and functional in the temperature ranges in which their host organisms live and grow, are still only partially elucidated. Indeed, both experimental and computational studies fail to yield a fully precise and global physical picture, essentially because all effects are context-dependent and thus quite intricate to unravel. We present a snapshot of the current state of knowledge of this highly complex and challenging issue, whose resolution would enable large-scale rational protein design...
December 29, 2016: Current Opinion in Structural Biology
Loukas I Goulatis, Eric V Shusta
The blood brain barrier (BBB) presents a challenge for the delivery of brain therapeutics. Trans-BBB delivery methods that use targeting vectors to coopt the vesicle trafficking machinery of BBB endothelial cells have been developed, but these are often hampered by limited flux through the BBB. A solution to this problem lies in the semi-rational engineering of BBB targeting vectors. Leveraging knowledge of intracellular trafficking, researchers have begun to tune selected binding properties of the vector-receptor interaction...
December 29, 2016: Current Opinion in Structural Biology
Kelli Kazmier, Derek P Claxton, Hassane S Mchaourab
Secondary active transporters couple the uphill translocation of substrates to electrochemical ion gradients. Transporter conformational motion, generically referred to as alternating access, enables a central ligand binding site to change its orientation relative to the membrane. Here we review themes of alternating access and the transduction of ion gradient energy to power this process in the LeuT-fold class of transporters where crystallographic, computational and spectroscopic approaches have converged to yield detailed models of transport cycles...
December 29, 2016: Current Opinion in Structural Biology
Matthew G Eason, Adam M Damry, Roberto A Chica
Red fluorescent proteins (RFPs) have become an integral part of modern biological research due to their longer excitation and emission wavelengths. Protein engineering efforts have improved many key properties of RFPs for their practical use in imaging. Even so, continued engineering is required to overcome the shortcomings of the red chromophore and create RFPs with photophysical properties rivalling those of their optimized green and yellow counterparts. Here, we highlight recent examples of structure-guided rational design of RFPs to improve brightness, monomerization, maturation, and photostability, and discuss possible pathways for the future engineering of designer RFPs tailored to specific applications...
December 27, 2016: Current Opinion in Structural Biology
Harold P Erickson
Extracellular matrix fibrils of fibronectin (FN) are highly elastic, and are typically stretched three to four times their relaxed length. The mechanism of stretching has been controversial, in particular whether it involves tension-induced unfolding of FNIII domains. Recent studies have found that ∼5pN is the threshold isometric force for unfolding various protein domains. FNIII domains should therefore not be unfolded until the tension approaches 5pN. Integrins have been reported to generate forces ranging from 1 to >50pN, but I argue that studies reporting 1-2pN are the most convincing...
December 27, 2016: Current Opinion in Structural Biology
Rafael J Najmanovich
Biological processes at their most fundamental molecular aspects are defined by molecular interactions with ligand-protein interactions in particular at the core of cellular functions such as metabolism and signalling. Divergent and convergent processes shape the evolution of ligand binding sites. The competition between similar ligands and binding sites across protein families create evolutionary pressures that affect the specificity and selectivity of interactions. This short review showcases recent studies of the evolution of ligand binding-sites and methods used to detect binding-site similarities...
December 16, 2016: Current Opinion in Structural Biology
Zachary A Levine, Joan-Emma Shea
Intrinsically disordered proteins (IDPs) and protein regions can facilitate a wide variety of complex physiological processes such as binding, signaling, and formation of membraneless organelles. They can however also play pathological roles by aggregating into cytotoxic oligomers and fibrils. Characterizing the structure and function of disordered proteins is an onerous task, primarily because these proteins adopt transient structures, which are difficult to capture in experiments. Simulations have emerged as a powerful tool for interpreting and augmenting experimental measurements of IDPs...
December 15, 2016: Current Opinion in Structural Biology
Thomas Clairfeuille, Hui Xu, Christopher M Koth, Jian Payandeh
Voltage-gated sodium (Nav) channels initiate and propagate action potentials in excitable cells, and are frequently dysregulated or mutated in human disease. Despite decades of intense physiological and biophysical research, eukaryotic Nav channels have so far eluded high-resolution structure determination because of their biochemical complexity. Recently, simpler bacterial voltage-gated sodium (BacNav) channels have provided templates to understand the structural basis of voltage-dependent activation, inactivation, ion selectivity, and drug block in eukaryotic Nav and related voltage-gated calcium (Cav) channels...
December 15, 2016: Current Opinion in Structural Biology
Lillian T Chong, Ali S Saglam, Daniel M Zuckerman
Despite more than three decades of effort with molecular dynamics simulations, long-timescale (ms and beyond) biologically relevant phenomena remain out of reach in most systems of interest. This is largely because important transitions, such as conformational changes and (un)binding events, tend to be rare for conventional simulations (<10μs). That is, conventional simulations will predominantly dwell in metastable states instead of making large transitions in complex biomolecular energy landscapes. In contrast, path sampling approaches focus computing effort specifically on transitions of interest...
December 13, 2016: Current Opinion in Structural Biology
Eviatar Natan, Jonathan N Wells, Sarah A Teichmann, Joseph A Marsh
Most proteins assemble into complexes, which are involved in almost all cellular processes. Thus it is crucial for cell viability that mechanisms for correct assembly exist. The timing of assembly plays a key role in determining the fate of the protein: if the protein is allowed to diffuse into the crowded cellular milieu, it runs the risk of forming non-specific interactions, potentially leading to aggregation or other deleterious outcomes. It is therefore expected that strong regulatory mechanisms should exist to ensure efficient assembly...
December 12, 2016: Current Opinion in Structural Biology
Wei Yang, Luhua Lai
Custom-designed ligand-binding proteins with novel functions hold the potential for numerous applications. In recent years, the developments of computational methods together with high-throughput experimental screening techniques have led to the generation of novel, high-affinity ligand-binding proteins for given ligands. In addition, naturally occurring ligand-binding proteins have been computationally designed to recognize new ligands while keeping their original biological functions at the same time. Furthermore, metalloproteins have been successfully designed for novel functions and applications...
December 9, 2016: Current Opinion in Structural Biology
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