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Cathy J Anderson, Matthew R Baird, Allen Hsu, Emily H Barbour, Yuka Koyama, Mario J Borgnia, Robert K McGinty
Histone H3 lysine 79 (H3K79) methylation is enriched on actively transcribed genes, and its misregulation is a hallmark of leukemia. Methylation of H3K79, which resides on the structured disk face of the nucleosome, is mediated by the Dot1L methyltransferase. Dot1L activity is part of a trans-histone crosstalk pathway, requiring prior histone H2B ubiquitylation of lysine 120 (H2BK120ub) for optimal activity. However, the molecular details describing both how Dot1L binds to the nucleosome and why Dot1L is activated by H2BK120 ubiquitylation are unknown...
February 12, 2019: Cell Reports
Glen McHale, Bethany V Orme, Gary George Wells, Rodrigo Andres Ledesma-Aguilar
A fundamental limitation of liquids on many surfaces is their contact line pinning. This limitation can be overcome by infusing a non-volatile and immiscible liquid or lubricant into texture or roughness created in or applied onto the solid substrate so that the liquid of interest no longer directly contacts the underlying surface. Such slippery liquid infused porous surfaces (SLIPS), also known as lubricant impregnated surfaces, complete remove contact line pinning and contact angle hysteresis. However, although a sessile droplet may rest on such a surface, its contact angle can only be an apparent contact angle because its contact is now with a second liquid and not a solid...
February 13, 2019: Langmuir: the ACS Journal of Surfaces and Colloids
Tharindu Senapathi, Simon Bray, Christopher B Barnett, Björn Grüning, Kevin J Naidoo
Motivation: The pathway from genomics through proteomics and onto a molecular description of biochemical processes make the discovery of drugs and biomaterials possible. A research framework common to genomics and proteomics is needed to conduct biomolecular simulations that will connect biological data to the dynamic molecular mechanisms of enzymes and proteins. Novice biomolecular modelers are faced with the daunting task of complex setups and a myriad of possible choices preventing their use of molecular simulations and their ability to conduct reliable and reproducible computations that can be shared with collaborators and verified for procedural accuracy...
February 13, 2019: Bioinformatics
Debswapna Bhattacharya
Motivation: Protein structure refinement aims to bring moderately accurate template-based protein models closer to the native state through conformational sampling. However, guiding the sampling towards the native state by effectively using restraints remains a major issue in structure refinement. Results: Here, we develop a machine learning based restrained relaxation protocol that uses deep discriminative learning based binary classifiers to predict multi-resolution probabilistic restraints from the starting structure and subsequently converts these restraints to be integrated into Rosetta all-atom energy function as additional scoring terms during structure refinement...
February 13, 2019: Bioinformatics
Lisa N van der Vorm, Li Li, Dana Huskens, Walid Chayouâ, Hilde Kelchtermans, Philip G de Groot, Mark Roest, Jasper A Remijn, Bas de Laat
BACKGROUND: Interaction of von Willebrand factor (VWF) with platelets requires a conformational change that exposes an epitope within the VWF A1 domain, enabling platelet glycoprotein Ibα binding. Quantification of this ''active" conformation of VWF has been shown to provide pathophysiological insight into conditions characterized by excessive VWF-platelet interaction. METHODS: We developed an immunosorbent assay based on a variable heavy chain antibody fragment against the VWF A1 domain as a capture antibody...
2019: PloS One
Sandip K Nandi, Stefan Rakete, Rooban B Nahomi, Cole Robert Michel, Alexandra Dunbar, Kristofer S Fritz, Ram H Nagaraj
Acylation of lysine residues is a common post-translational modification of cellular proteins. Here, we show that lysine succinylation, a type of acylation, occurs in human lens proteins. All the major crystallins exhibited Nε -succinyllysine (SuccK) residues. Quantification of SuccK in human lens proteins (from donors between the ages of 20 and 73 years) by LC-MS/MS showed a range between 1.2 and 14.3 pmol/mg lens protein. The total SuccK levels were slightly reduced in aged lenses (age > 60 years) relative to young lenses (age < 30 years)...
February 13, 2019: Biochemistry
Jingjing Xu, Franck Merlier, Bérangère Avalle, Vincent Vieillard, Patrice Debré, Karsten Haupt, Bernadette Tse Sum Bui
We describe the preparation and characterization of synthetic antibodies based on molecularly imprinted polymer nanoparticles (MIP-NPs), for the recognition and binding of the highly conserved and specific peptide motif SWSNKS (3S), an epitope of the envelope glycoprotein 41 (gp41) of human immunodeficiency virus type 1 (HIV-1). This motif is implicated in the decline of CD4+ T cells and leads to the deterioration of the immune system during HIV infection. Therefore, the development of MIP-NPs that can target and block the 3S peptide to prevent subsequent cascade interactions directed toward the killing of CD4+ T cells is of prime importance...
February 13, 2019: ACS Applied Materials & Interfaces
Serena Carra, Simon Alberti, Justin L P Benesch, Wilbert Boelens, Johannes Buchner, John A Carver, Ciro Cecconi, Heath Ecroyd, Nikolai Gusev, Lawrence E Hightower, Rachel E Klevit, Hyun O Lee, Krzysztof Liberek, Brent Lockwood, Angelo Poletti, Vincent Timmerman, Melinda E Toth, Elizabeth Vierling, Tangchun Wu, Robert M Tanguay
Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archaea, bacteria, and eukaryota. sHSPs belong to the superfamily of molecular chaperones: they are components of the cellular protein quality control machinery and are thought to act as the first line of defense against conditions that endanger the cellular proteome. In plants, sHSPs protect cells against abiotic stresses, providing innovative targets for sustainable agricultural production. In humans, sHSPs (also known as HSPBs) are associated with the development of several neurological diseases...
February 13, 2019: Cell Stress & Chaperones
Alexander Negoda, Mairin S Hogan, Elizabeth A Cowley, Paul Linsdell
Our molecular understanding of the cystic fibrosis transmembrane conductance regulator (CFTR)-the chloride channel that is mutated in cystic fibrosis-has been greatly enhanced by a number of recent atomic-level structures of the protein in different conformations. One surprising aspect of these structures was the finding that the eighth of CFTR's 12 membrane-spanning segments (TM8) appeared close to the channel pore. Although functional evidence supports a role for other TMs in forming the pore, such a role for TM8 has not previously been reported...
February 13, 2019: Cellular and Molecular Life Sciences: CMLS
Charleston Ribeiro Pinto, Antônio Carlos Moreira Lemos, Lindemberg Assunção-Costa, Aramis Tupiná de Alcântara, Laira Lorena Lima Yamamura, Gisélia Santana Souza, Eduardo Martins Netto
OBJECTIVE: To describe COPD pharmacological treatment patterns in the state of Bahia, Brazil, and to evaluate the extent to which these patterns conform to clinical guidelines for the management of COPD. METHODS: This was a cross-sectional study of 441 patients referred from the Public Health Care Network of the state of Bahia to a public referral outpatient clinic of a COPD management program of the Brazilian Unified Health Care System. Individuals with a spirometry-confirmed diagnosis of moderate to very severe COPD were included in the study...
February 11, 2019: Jornal Brasileiro de Pneumologia: Publicaça̋o Oficial da Sociedade Brasileira de Pneumologia e Tisilogia
Prashant Kumar Gupta, Alexander Esser, Harald Forbert, Dominik Marx
The molecular-level understanding of THz spectra of aqueous solutions under ambient conditions has been greatly advanced in recent years. Here, we go beyond previous analyses by performing ab initio molecular dynamics simulations of glycine in water with artificially frozen solute or solvent molecules, respectively, while computing the total THz response as well as its decomposition into mode-specific resonances based on the "supermolecular solvation complex" technique. Clamping the water molecules and keeping glycine moving breaks the coupling of glycine to the structural dynamics of the solvent, however, the polarization and dielectric solvation effects in the static solvation cage are still at work since the full electronic structure of the quenched solvent is taken into account...
February 13, 2019: Physical Chemistry Chemical Physics: PCCP
Santosh K Singh, Shahaji More, Satish Kumar, Kamal K Mishra, Krishna N Ganesh, Aloke Das
Collagen, the most abundant protein in animals, has a unique triple helical structure comprising three parallel left-handed polyproline II (PPII) strands while each of the strands consists of a repeating sequence of X-Y-Gly, where X = proline (Pro) and Y = 4-hydroxyproline (Hyp). Collagen forms a stable triple helix of very long polypeptide strands despite the absence of intra-strand hydrogen bonding in the individual polypeptide chains. It has been reported that non-covalent n→π* interaction plays a significant role in stabilizing the individual polypeptide strands in collagen...
February 13, 2019: Physical Chemistry Chemical Physics: PCCP
Elizabeth G Gibson, Ben Bax, Pan F Chan, Neil Osheroff
Gepotidacin is a first-in-class triazaacenaphthylene novel bacterial topoisomerase inhibitor (NBTI). The compound has successfully completed phase II trials for the treatment of acute bacterial skin/skin structure infections and for the treatment of uncomplicated urogenital gonorrhea. It also displays robust in vitro activity against a range of wild-type and fluoroquinolone-resistant bacteria. Due to the clinical promise of gepotidacin, a detailed understanding of its interactions with its antibacterial targets is essential...
February 13, 2019: ACS Infectious Diseases
Karolina Gaweda, Wojciech Plazinski
The endo- and exo-anomeric effects are the two most recognizable stereoelectronic effects exhibited by carbohydrates. Their presence relies on the interactions between ring substituent(s) and ring oxygen atoms. Here, we report the finding of a new effect that partially controls the conformational properties of furanose rings and can be ascribed to the influence of the solvent on the electronic structure of a molecule. In contrast to anomeric effects, it is not dependent on either presence or absence of ring substituents...
February 13, 2019: Organic & Biomolecular Chemistry
Nicholas G Campbell, Aparna Shekar, Jenny I Aguilar, Dungeng Peng, Vikas Navratna, Dongxue Yang, Alexander N Morley, Amanda M Duran, Greta Galli, Brian O'Grady, Ramnarayan Ramachandran, James S Sutcliffe, Harald H Sitte, Kevin Erreger, Jens Meiler, Thomas Stockner, Leon M Bellan, Heinrich J G Matthies, Eric Gouaux, Hassane S Mchaourab, Aurelio Galli
The human dopamine (DA) transporter (hDAT) mediates clearance of DA. Genetic variants in hDAT have been associated with DA dysfunction, a complication associated with several brain disorders, including autism spectrum disorder (ASD). Here, we investigated the structural and behavioral bases of an ASD-associated in-frame deletion in hDAT at N336 (∆N336). We uncovered that the deletion promoted a previously unobserved conformation of the intracellular gate of the transporter, likely representing the rate-limiting step of the transport process...
February 12, 2019: Proceedings of the National Academy of Sciences of the United States of America
Erika Ponzini, Antonella De Palma, Lucilla Cerboni, Antonino Natalello, Rossana Rossi, Rani Moons, Albert Konijnenberg, Joanna Narkiewicz, Giuseppe Antonio Legname, Frank Sobott, Pierluigi Mauri, Carlo Santambrogio, Rita Grandori
α-Synuclein (AS) is an intrinsically disordered protein highly expressed in dopaminergic neurons. Its amyloid aggregates are the major component of Lewy bodies, a hallmark of Parkinson's disease (PD). AS is particularly exposed to oxidation of its methionine residues, both in vivo and in vitro. Oxidative stress has been implicated in PD and oxidized α-synuclein has been shown to assemble into soluble, toxic oligomers, rather than amyloid fibrils. However, the structural effects of methionine oxidation are still poorly understood...
February 12, 2019: Journal of Biological Chemistry
Anne Wentink, Carmen Nussbaum-Krammer, Bernd Bukau
Aberrant protein aggregation is a defining feature of most neurodegenerative diseases. During pathological aggregation, key proteins transition from their native state to alternative conformations, which are prone to oligomerize into highly ordered fibrillar states. As part of the cellular quality control machinery, molecular chaperones can intervene at many stages of the aggregation process to inhibit or reverse aberrant protein aggregation or counteract the toxicity associated with amyloid species. Although the action of chaperones is considered cytoprotective, essential housekeeping functions can be hijacked for the propagation and spreading of protein aggregates, suggesting the cellular protein quality control system constitutes a double-edged sword in neurodegeneration...
February 12, 2019: Cold Spring Harbor Perspectives in Biology
Kuan-Lin Chen, Yen-Hua Huang, Jen-Fu Liao, Wei-Chen Lee, Cheng-Yang Huang
DnaT is a replication restart primosomal protein required for re-initiating chromosomal DNA replication in bacteria. DnaT can be a monomer, dimer, trimer, tetramer, or pentamer. The oligomerization and disassembly of DnaT oligomers are critical in primosome assembly. Prior to this work, only the ssDNA-bound structure of the pentameric DnaT truncated protein (aa 84-153; DnaT84-153) was available. The mechanism by which DnaT oligomerizes as different states is unclear. In this paper, we report the crystal structure of the C-terminal domain of DnaT (aa 84-179; DnaTc) at 2...
February 9, 2019: Biochemical and Biophysical Research Communications
Milka Doktorova, Frederick A Heberle, Drew Marquardt, Radda Rusinova, R Lea Sanford, Thasin A Peyear, John Katsaras, Gerald W Feigenson, Harel Weinstein, Olaf S Andersen
Unlike most transmembrane proteins, phospholipids can migrate from one leaflet of the membrane to the other. Because this spontaneous lipid translocation (flip-flop) tends to be very slow, cells facilitate the process with enzymes that catalyze the transmembrane movement and thereby regulate the transbilayer lipid distribution. Nonenzymatic membrane-spanning proteins with unrelated primary functions have also been found to accelerate lipid flip-flop in a nonspecific manner and by various hypothesized mechanisms...
January 25, 2019: Biophysical Journal
Rudy Sangaletti, Andrea Spreafico, Flavio Barbieri, Roberto Ferrari, Claudio Carlo Castelli
INTRODUCTION: There have been reported adverse reactions in patients with large head metal-on-metal hip arthroplasty, therefore metal particle debris are a cause for concern. The aim of this study was to evaluate the release trend of metal ions and the correlated variables. METHODS: 54 patients were prospectively enrolled into the study from 2004 to 2006. All patients had 36-mm metal head, Pinnacle acetabular component, Summit stem and Ultamet CoCr alloy liner (Depuy Inc...
November 2018: Hip International: the Journal of Clinical and Experimental Research on Hip Pathology and Therapy
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