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Current Opinion in Structural Biology

Passainte Ibrahim, Timothy Clark
Recent developments in metadynamics simulation techniques for ligand binding to Class A GPCRs are described and the results obtained elucidated. The computational protocol makes good use of modern massively parallel hardware, making simulations of the binding/unbinding process routine. The simulations reveal unprecedented details of the ligand-binding pathways, including multiple binding sites in many cases. Free energies of binding are reproduced very well and the simulations allow prediction of the efficacy (agonist, antagonist etc...
May 14, 2019: Current Opinion in Structural Biology
João Marcelo Lamim Ribeiro, Marta Filizola
G-protein-coupled receptors (GPCRs) are allosteric signaling machines that trigger distinct functional responses depending on the particular conformational state they adopt upon binding. This so-called GPCR functional selectivity is prompted by ligands of different efficacy binding at orthosteric or allosteric sites on the receptor, as well as by interactions with intracellular protein partners or other receptor types. Molecular dynamics (MD) simulations can provide important mechanistic, thermodynamic, and kinetic insights into these interactions at a level of molecular detail that is necessary to rightly inform modern drug discovery...
May 13, 2019: Current Opinion in Structural Biology
Serdar Durdagi, Berna Dogan, Ismail Erol, Gülru Kayık, Busecan Aksoydan
Membrane receptors couple signaling pathways using various mechanisms. G Protein-Coupled Receptors (GPCRs) represent the largest class of membrane proteins involved in signal transduction across the biological membranes. They are essential targets for cell signaling and are of great commercial interest to the pharmaceutical industry. Recent advances made in molecular biology and computational chemistry offer a range of simulation and multiscale modeling tools for the definition and analysis of protein-ligand, protein-protein, and protein-membrane interactions...
May 10, 2019: Current Opinion in Structural Biology
Slawomir Filipek
Molecular switches in GPCRs enable passing the signal from the agonist binding site, usually located close to the extracellular surface, to the intracellular part of the receptor. The switches are usually associated with conserved structural motifs on transmembrane helices (TMs), and they are accompanied by adjacent residues which provide the signal to the central residue in the toggle switch. In case of locks being the molecular switches, they are breaking (permanently or temporarily) upon agonist binding...
May 10, 2019: Current Opinion in Structural Biology
Jan Deubner, Philippe Coulon, Ilka Diester
Optogenetics has revolutionized neurobiological research by allowing to disentangle intricate neuronal circuits at a spatio-temporal precision unmatched by other techniques. Here, we review current advances of optogenetic applications in mammals, especially focusing on freely moving animals. State-of-the-art strategies allow the targeted expression of opsins in neuronal subpopulations, defined either by genetic cell type or neuronal projection pattern. Optogenetic manipulations of these subpopulations become particularly powerful when combined with behavioral paradigms and neurophysiological readout techniques...
May 10, 2019: Current Opinion in Structural Biology
Michael Koomey
Bacterial protein glycosylation (BPG) comes in all variations of form and manifestation: N-versus O-linked, dedicated versus broad-spectrum, sequential versus en bloc glycan addition, cytoplasmic versus extracytoplasmic. Here, I evaluate and address recent advances in the field of O-linked BPG focusing on selected systems of notoriety and in which significant advances have occurred of late.
May 9, 2019: Current Opinion in Structural Biology
B A Wallace
Circular dichroism (CD) spectroscopy has been used widely in structural biology for literally a half century, primarily to examine the secondary structure, folding, and interactions of proteins in solution. With recent developments in instrumentation, it is now possible to apply CD to many additional types of sample environments, including oriented membranes, films, and dehydrated samples. In addition, developments in bioinformatics have made validated CD spectra and metadata available for novel analysis methods on additional types of samples such as membrane proteins, intrinsically disordered proteins, multiple fold types, and multicomponent, macromolecular complexes...
May 8, 2019: Current Opinion in Structural Biology
Mark J Bostock, Andras S Solt, Daniel Nietlispach
Over recent years, nuclear magnetic resonance (NMR) spectroscopy has developed into a powerful mechanistic tool for the investigation of G protein-coupled receptors (GPCRs). NMR provides insights which underpin the dynamic nature of these important receptors and reveals experimental evidence for a complex conformational energy landscape that is explored during receptor activation resulting in signalling. NMR studies have highlighted both the dynamic properties of different receptor states as well as the exchange pathways and intermediates formed during activation, extending the static view of GPCRs obtained from other techniques...
May 7, 2019: Current Opinion in Structural Biology
Zhen Li, Wengang Chai
The study of mucin O-glycan recognition by glycan-binding proteins has been a challenging area of research at the interface of chemistry and biology. Compared with N-glycans, the development of methods for mucin O-glycans has lagged behind and underrepresentation of O-glycans in any of the current microarray libraries have hampered their application in O-glycan recognition studies. A major reason is that, thus far, there has not been a universal O-glycanase for enzymatic release of O-glycans from mucins. Methods of chemical release result in degradation or modification of the core regions...
May 4, 2019: Current Opinion in Structural Biology
Francesca Magnani, Andrea Mattevi
NADPH oxidases (NOXs) are integral membrane enzymes that produce reactive oxygen species. Humans have seven NOX enzymes that feature a very similar catalytic core but distinct regulatory mechanisms. The recent structural elucidation of the NOX catalytic domains has been a step forward in the field. NADPH, FAD, and two hemes form a linear array of redox cofactors that transfer electrons across to the two sides of the membrane. Oxygen is reduced through an unusual outer sphere mechanism that does not involve any covalent intermediate with the heme iron...
April 30, 2019: Current Opinion in Structural Biology
Jonathan J Ruprecht, Edmund Rs Kunji
The mitochondrial ADP/ATP carrier, also called adenine nucleotide translocase, accomplishes one of the most important transport activities in eukaryotic cells, importing ADP into the mitochondrial matrix for ATP synthesis, and exporting ATP to fuel cellular activities. In the transport cycle, the carrier changes between a cytoplasmic and matrix state, in which the central substrate binding site is alternately accessible to these compartments. A structure of a cytoplasmic state was known, but recently, a structure of a matrix-state in complex with bongkrekic acid was solved...
April 27, 2019: Current Opinion in Structural Biology
Venkata S Mandala, Mei Hong
The sensitivity of solid-state nuclear magnetic resonance (SSNMR) spectroscopy for structural biology is significantly increased by 1 H detection under fast magic-angle spinning (MAS) and by dynamic nuclear polarization (DNP) from electron spins to nuclear spins. The former allows studies of the structure and dynamics of small quantities of proteins under physiological conditions, while the latter permits studies of large biomolecular complexes in lipid membranes and cells, protein intermediates, and protein conformational distributions...
April 25, 2019: Current Opinion in Structural Biology
Faruck Morcos, José N Onuchic
Evolution imposes constraints at the interface of interacting biomolecules in order to preserve function or maintain fitness. This pressure may have a direct effect on the sequence composition of interacting biomolecules. As a result, statistical patterns of amino acid or nucleotide covariance that encode for physical and functional interactions are observed in sequences of extant organisms. In recent years, global pairwise models of amino acid and nucleotide coevolution from multiple sequence alignments have been developed and utilized to study molecular interactions in structural biology...
April 25, 2019: Current Opinion in Structural Biology
Amnon Horovitz, Rachel C Fleisher, Tridib Mondal
Double-mutant cycle (DMC) analysis is a powerful approach for detecting and quantifying the energetics of both direct and long-range interactions in proteins and other chemical systems. It can also be used to unravel higher-order interactions (e.g. three-body effects) that lead to cooperativity in protein folding and function. In this review, we describe new applications of DMC analysis based on advances in native mass spectrometry and high-throughput methods such as next generation sequencing and protein complementation assays...
April 25, 2019: Current Opinion in Structural Biology
Alexander Heifetz, Tim James, Michelle Southey, Inaki Morao, Matteo Aldeghi, Laurie Sarrat, Dmitri G Fedorov, Mike J Bodkin, Andrea Townsend-Nicholson
There has been fantastic progress in solving GPCR crystal structures. However, the ability of X-ray crystallography to guide the drug discovery process for GPCR targets is limited by the availability of accurate tools to explore receptor-ligand interactions. Visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum mechanical approaches (QM) are often too computationally expensive, but the fragment molecular orbital (FMO) method offers an excellent solution that combines accuracy, speed and the ability to reveal key interactions that would otherwise be hard to detect...
April 22, 2019: Current Opinion in Structural Biology
Florian Km Schur
Cryo-electron tomography (cryo-ET) provides unprecedented insights into the molecular constituents of biological environments. In combination with an image processing method called subtomogram averaging (STA), detailed 3D structures of biological molecules can be obtained in large, irregular macromolecular assemblies or in situ, without the need for purification. The contextual meta-information these methods also provide, such as a protein's location within its native environment, can then be combined with functional data...
April 18, 2019: Current Opinion in Structural Biology
Kevin A Cannon, Jessica M Ochoa, Todd O Yeates
The accelerated elucidation of three-dimensional structures of protein complexes, both natural and designed, is providing new examples of large supramolecular assemblies with intriguing shapes. Those with high symmetry - based on the geometries of the Platonic solids - are particularly notable as their innately closed forms create interior spaces with varying degrees of enclosure. We survey known protein assemblies of this type and discuss their geometric features. The results bear on issues of protein function and evolution, while also guiding novel bioengineering applications...
April 18, 2019: Current Opinion in Structural Biology
Amara Jabeen, Shoba Ranganathan
GPCRs constitute the largest druggable family having targets for 475 Food and Drug Administration (FDA) approved drugs. As GPCRs are of great interest to pharmaceutical industry, enormous efforts are being expended to find relevant and potent GPCR ligands as lead compounds. There are tens of millions of compounds present in different chemical databases. In order to scan this immense chemical space, computational methods, especially machine learning (ML) methods, are essential components of GPCR drug discovery pipelines...
April 18, 2019: Current Opinion in Structural Biology
Norman E Davey
After two decades of research, intrinsically disordered regions (IDRs) are established as a widespread phenomenon. The growing understanding of the significant functional role of IDRs has challenged the structure-function paradigm, proving irrefutably that a stably folded structure is not a strict requirement for function. Nonetheless, (un)structure-function relationships remain at the core of IDR-mediated interactions. An IDR can populate a continuously transitioning continuum of structural conformations from fully disordered to stable globular states...
April 16, 2019: Current Opinion in Structural Biology
Karen N Allen, Barbara Imperiali
Peripheral and integral membrane proteins feature in stepwise assembly of complex glycans and glycoconjugates. Catalysis on membrane-bound substrates features challenges with substrate solubility and active-site accessibility. However, advantages in enzyme and substrate orientation and control of lateral membrane diffusion provide order to the multistep processes. Recent glycosyltransferase (GT) studies show that substrate diversity is met by the selection of folds which do not converge upon a common mechanism...
April 16, 2019: Current Opinion in Structural Biology
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