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Protein structure prediction

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https://www.readbyqxmd.com/read/28641268/newgoa-predicting-new-go-annotations-of-proteins-by-bi-random-walks-on-a-hybrid-graph
#1
Guoxian Yu, Guangyuan Fu, Jun Wang, Yingwen Zhao
A remaining key challenge of modern biology is annotating the functional roles of proteins. Various computational models have been proposed for this challenge. Most of them assume the annotations of annotated proteins are complete. But in fact, many of them are incomplete. We proposed a method called NewGOA to predict new Gene Ontology (GO) annotations for incompletely annotated proteins and for completely un-annotated ones. NewGOA employs a hybrid graph, composed of two types of nodes (proteins and GO terms), to encode interactions between proteins, hierarchical relationships between terms and available annotations of proteins...
June 15, 2017: IEEE/ACM Transactions on Computational Biology and Bioinformatics
https://www.readbyqxmd.com/read/28641111/structural-insights-into-modulation-of-neurexin-neuroligin-trans-synaptic-adhesion-by-mdga1-neuroligin-2-complex
#2
Jung A Kim, Doyoun Kim, Seoung Youn Won, Kyung Ah Han, Dongseok Park, Eunju Cho, Nayoung Yun, Hyun Joo An, Ji Won Um, Eunjoon Kim, Jie-Oh Lee, Jaewon Ko, Ho Min Kim
Membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins (MDGAs) bind directly to neuroligin-1 (NL1) and neuroligin-2 (NL2), thereby respectively regulating excitatory and inhibitory synapse development. However, the mechanisms by which MDGAs modulate NL activity to specify development of the two synapse types remain unclear. Here, we determined the crystal structures of human NL2/MDGA1 Ig1-3 complex, revealing their stable 2:2 arrangement with three interaction interfaces. Cell-based assays using structure-guided, site-directed MDGA1 mutants showed that all three contact patches were required for the MDGA's negative regulation of NL2-mediated synaptogenic activity...
June 21, 2017: Neuron
https://www.readbyqxmd.com/read/28640808/transmembrane-helical-interactions-in-the-cftr-channel-pore
#3
Jhuma Das, Andrei A Aleksandrov, Liying Cui, Lihua He, John R Riordan, Nikolay V Dokholyan
Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene affect CFTR protein biogenesis or its function as a chloride channel, resulting in dysregulation of epithelial fluid transport in the lung, pancreas and other organs in cystic fibrosis (CF). Development of pharmaceutical strategies to treat CF requires understanding of the mechanisms underlying channel function. However, incomplete 3D structural information on the unique ABC ion channel, CFTR, hinders elucidation of its functional mechanism and correction of cystic fibrosis causing mutants...
June 22, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28636950/structural-evidence-of-quercetin-multi-target-bioactivity-a-reverse-virtual-screening-strategy
#4
Diego Carvalho, Margot Paulino, Fabio Polticelli, Florencia Arredondo, Robert J Williams, Juan A Abin-Carriquiry
The ubiquitous flavonoid quercetin is broadly recognized for showing diverse biological and health-promoting effects, such as anti-cancer, anti-inflammatory and cytoprotective activities. The therapeutic potential of quercetin and similar compounds for preventing such diverse oxidative stress-related pathologies has been generally attributed to their direct antioxidant properties. Nevertheless, accumulated evidence indicates that quercetin is also able to interact with multiple cellular targets influencing the activity of diverse signaling pathways...
June 18, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28636918/actin-filament-strain-promotes-severing-and-cofilin-dissociation
#5
Anthony C Schramm, Glen M Hocky, Gregory A Voth, Laurent Blanchoin, Jean-Louis Martiel, Enrique M De La Cruz
Computational and structural studies have been indispensable in investigating the molecular origins of actin filament mechanical properties and modulation by the regulatory severing protein cofilin. All-atom molecular dynamics simulations of cofilactin filament structures determined by electron cryomicroscopy reveal how cofilin enhances the bending and twisting compliance of actin filaments. Continuum mechanics models suggest that buckled cofilactin filaments localize elastic energy at boundaries between bare and cofilin-decorated segments because of their nonuniform elasticity, thereby accelerating filament severing...
June 20, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28636361/a-machine-learning-assisted-approach-for-discovering-novel-inhibitors-targeting-bromodomain-containing-protein-4
#6
Jing Xing, Wenchao Lu, Rongfeng Liu, Yulan Wang, Yiqian Xie, Hao Zhang, Zhe Shi, Hao Jiang, Yu-Chih Liu, Kaixian Chen, Hualiang Jiang, Cheng Luo, Mingyue Zheng
Bromodomain-containing protein 4 (BRD4) is implicated in the pathogenesis of a number of different cancers, inflammatory diseases and heart failure. Much effort has been dedicated toward discovering novel scaffold BRD4 inhibitors (BRD4is) with different selectivity profiles and potential anti-resistance properties. Structure-based drug design (SBDD) and virtual screening (VS) are the most frequently used approaches. Here, we demonstrate a novel, structure-based VS approach that uses machine-learning algorithms trained on the priori structure and activity knowledge to predict the likelihood that a compound is a BRD4i based on its binding pattern with BRD4...
June 21, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28634279/in-frame-seven-amino-acid-duplication-in-aip-arose-over-the-last-3000-years-disrupts-protein-interaction-stability-and-is-associated-with-gigantism
#7
Roberto Salvatori, Serban Radian, Yoan Diekmann, Donato Iacovazzo, Alessia David, Plamena Grabovska, Giorgia Grassi, Anna-Marie Bussell, Karen Stals, Astrid Weber, Richard Quinton, Elizabeth Crowne, Valentina Corazzini, Louise A Metherell, Tara Kearney, Daniel Du Plessis, Ajay Sinha, Atik Baborie, Anne-LIse Locoq, Philippe Chanson, Olaf Ansorge, Sian Ellard, Peter J Trainer, David Balding, Mark Thomas, Marta Korbonits
OBJECTIVE: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. DESIGN & METHODS: Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments...
June 20, 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/28634046/tumor-antigen-prame-is-up-regulated-by-mzf1-in-cooperation-with-dna-hypomethylation-in-melanoma-cells
#8
Yong-Kyu Lee, Ui-Hyun Park, Eun-Joo Kim, Jin-Taek Hwang, Ji-Cheon Jeong, Soo-Jong Um
Elevated expression of preferentially expressed antigen in melanoma (PRAME) has been implicated in disease progression in a variety of cancers. However, the mechanisms underlying the transcriptional regulation of PRAME remain largely unexplored. Initially, we observed that PRAME was elevated in proportion to the malignant potential of melanoma cells. From the in silico prediction of PRAME gene structure, we identified the putative myeloid zinc finger 1 (MZF1) binding sites, which overlap with a CpG-rich region located in the first intron...
June 17, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28633528/the-binding-space-concept-a-new-approach-to-enhance-the-reliability-of-docking-scores-and-its-application-to-predicting-butyrylcholinesterase-bche-hydrolytic-activity
#9
Giulio Vistoli, Angelica Mazzolari, Bernard Testa, Alessandro Pedretti
Docking simulations are very popular approaches able to assess the capacity of a given ligand to interact with a target. Docking simulations are usually focused on a single best complex even though many studies showed that ligands retain a significant mobility within a binding pocket by assuming different binding modes all of which may contribute to the monitored ligand affinity. The present study describes an innovative concept, the binding space, which allows an exploration of the ligand mobility within the binding pocket by simultaneously considering several ligand poses as generated by docking simulations...
June 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28633522/molecular-dynamics-information-improves-cis-peptide-based-function-annotation-of-proteins
#10
Sreetama Das, Pratiti Bhadra, Suryanarayanarao Ramakumar, Debnath Pal
Cis-peptide bonds, whose occurrence in proteins is rare but evolutionarily conserved, are implicated to play an important role in protein function. This has led to their previous use in a homology-independent, fragment match-based protein function annotation method. However, proteins are not static molecules; dynamics is integral to their activity. This is nicely epitomized by the geometric isomerization of cis-peptide to trans form for molecular activity. Hence we have incorporated both static (cis-peptide) and dynamics information to improve the prediction of protein molecular function...
June 21, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28631593/a-denv-2-type-specific-monoclonal-antibody-binds-to-the-denv-complex-reactive-antigenic-site-on-envelope-protein-domain-3
#11
Vanessa V Sarathy, Trevor J Pitcher, Gregory D Gromowski, John T Roehrig, Alan D T Barrett
The Dengue virus (DENV) envelope (E) protein is the major component of the viral surface and is structurally subdivided into three domains, ED1, ED2 and ED3. ED3 elicits potent neutralizing antibodies and contains two major antigenic sites: the DENV-type-specific and DENV-complex-reactive antigenic sites. Each site is composed of a limited subset of residues that are required for monoclonal antibody (mAb) binding. Here we show that DENV-2-type-specific mAb 9A3D-8 utilizes the functionally critical residues K307, V308, K310, I312, P332, L387, L389 and N390 for ED3 binding...
June 20, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28630348/analysis-of-a-dual-domain-phosphoglycosyl-transferase-reveals-a-ping-pong-mechanism-with-a-covalent-enzyme-intermediate
#12
Debasis Das, Petr Kuzmic, Barbara Imperiali
Phosphoglycosyl transferases (PGTs) are integral membrane proteins with diverse architectures that catalyze the formation of polyprenol diphosphate-linked glycans via phosphosugar transfer from a nucleotide diphosphate-sugar to a polyprenol phosphate. There are two PGT superfamilies that differ significantly in overall structure and topology. The polytopic PGT superfamily, represented by MraY and WecA, has been the subject of many studies because of its roles in peptidoglycan and O-antigen biosynthesis. In contrast, less is known about a second, extensive superfamily of PGTs that reveals a core structure with dual domain architecture featuring a C-terminal soluble globular domain and a predicted N-terminal membrane-associated domain...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28628859/structural-and-functional-effects-of-nucleotide-variation-on-the-human-tb-drug-metabolizing-enzyme-arylamine-n-acetyltransferase-1
#13
Ruben Cloete, Wisdom A Akurugu, Cedric J Werely, Paul D van Helden, Alan Christoffels
The human arylamine N-acetyltransferase 1 (NAT1) enzyme plays a vital role in determining the duration of action of amine-containing drugs such as para-aminobenzoic acid (PABA) by influencing the balance between detoxification and metabolic activation of these drugs. Recently, four novel single nucleotide polymorphisms (SNPs) were identified within a South African mixed ancestry population. Modeling the effects of these SNPs within the structural protein was done to assess possible structure and function changes in the enzyme...
June 10, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28628649/insights-into-the-binding-mode-of-mek-type-iii-inhibitors-a-step-towards-discovering-and-designing-allosteric-kinase-inhibitors-across-the-human-kinome
#14
Zheng Zhao, Lei Xie, Philip E Bourne
Protein kinases are critical drug targets for treating a large variety of human diseases. Type-III kinase inhibitors have attracted increasing attention as highly selective therapeutics. Thus, understanding the binding mechanism of existing type-III kinase inhibitors provides useful insights into designing new type-III kinase inhibitors. In this work, we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors...
2017: PloS One
https://www.readbyqxmd.com/read/28627969/identification-of-potential-inhibitors-of-fasciola-gigantica-thioredoxin1-computational-screening-molecular-dynamics-simulation-and-binding-free-energy-studies
#15
Rohit Shukla, Harish Shukla, Parismita Kalita, Amit Sonkar, Tripti Pandey, Dev Bukhsh Singh, Awanish Kumar, Timir Tripathi
Fasciola gigantica is the causative organism of fascioliasis and is responsible for major economic losses in livestock production globally. F. gigantica thioredoxin1 (FgTrx1) is an important redox-active enzyme involved in maintaining the redox homeostasis in the cell. To identify a potential anti-fasciolid compound, we conducted a structure-based virtual screening of natural compounds from the ZINC database (n = 1,67,740) against the FgTrx1 structure. The ligands were docked against FgTrx1 and 309 ligands were found to have better docking score...
June 19, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28627775/ensemble-architecture-for-prediction-of-enzyme-ligand-binding-residues-using-evolutionary-information
#16
Priyadarshini P Pai, Rohit Kadam Dattatreya, Sukanta Mondal
Enzyme interactions with ligands are crucial for various biochemical reactions governing life. Over many years attempts to identify these residues for biotechnological manipulations have been made using experimental and computational techniques. The computational approaches have gathered impetus with the accruing availability of sequence and structure information, broadly classified into template-based and de novo methods. One of the predominant de novo methods using sequence information involves application of biological properties for supervised machine learning...
June 19, 2017: Molecular Informatics
https://www.readbyqxmd.com/read/28627439/mitochondrial-prohibitin-and-its-ubiquitination-during-spermatogenesis-of-the-swimming-crab-charybdis-japonica
#17
Ya-Ru Xu, Yun-Shu Fan, Wan-Xi Yang
It has been proposed that prohibitin (PHB) involved in multiple cellular functions, including cell proliferation, differentiation, apoptosis, senescence and carcinogenesis. Various cellular compartment location of PHB demonstrates its diverse roles. Based on the full-length sequence of PHB gene, we analyzed the deduced amino acid sequence and the predicted protein structure of this gene in the swimming crab Charybdis japonica. It shows that the structure and function of PHB are conservative. The expression level of PHB mRNA and protein in different tissues were analyzed by sqRT-PCR and western blot respectively, which showed its high expression in testis...
June 13, 2017: Gene
https://www.readbyqxmd.com/read/28625364/semi-quantitative-models-for-identifying-potent-and-selective-transthyretin-amyloidogenesis-inhibitors
#18
Stephen Connelly, David E Mortenson, Sungwook Choi, Ian A Wilson, Evan T Powers, Jeffery W Kelly, Steven M Johnson
Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state-thereby inhibiting amyloidogenesis...
May 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28625135/studying-interactions-of-drugs-with-cell-membrane-nutrient-transporters-new-frontiers-of-proteoliposome-nanotechnology
#19
Mariafrancesca Scalise, Michele Galluccio, Lorena Pochini, Lara Console, Maria Barile, Nicola Giangregorio, Annamaria Tonazzi, Cesare Indiveri
Transport systems are hydrophobic proteins localized in cell membranes where they mediate transmembrane flow of nutrients, ions and any other compounds essential for cell metabolism. More than 400 transporters of the SoLuteCarrier (SLC) group are present in human cells. Transporters take contacts also with xenobiotics, thus mediating absorption and/or interaction with these exogenous compounds. Since drugs belong to xenobiotics, transporters gained interest also in drug discovery. Transporters differentially expressed in pathological conditions are exploited as drug targets...
June 15, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28623886/epsilon-cp-using-deep-learning-to-combine-information-from-multiple-sources-for-protein-contact-prediction
#20
Kolja Stahl, Michael Schneider, Oliver Brock
BACKGROUND: Accurately predicted contacts allow to compute the 3D structure of a protein. Since the solution space of native residue-residue contact pairs is very large, it is necessary to leverage information to identify relevant regions of the solution space, i.e. correct contacts. Every additional source of information can contribute to narrowing down candidate regions. Therefore, recent methods combined evolutionary and sequence-based information as well as evolutionary and physicochemical information...
June 17, 2017: BMC Bioinformatics
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