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https://www.readbyqxmd.com/read/29166663/a-general-model-for-predicting-the-binding-affinity-of-reversibly-and-irreversibly-dimerized-ligands
#1
Kenneth W Foreman
Empirical data has shown that bivalent inhibitors can bind a given target protein significantly better than their monomeric counterparts. However, predicting the corresponding theoretical fold improvements has been challenging. The current work builds off the reacted-site probability approach to provide a straightforward baseline reference model for predicting fold-improvements in effective affinity of dimerized ligands over their monomeric counterparts. For the more familiar irreversibly linked bivalents, the model predicts a weak dependence on tether length and a scaling of the effective affinity with the 3/2 power of the monomer's affinity...
2017: PloS One
https://www.readbyqxmd.com/read/29166564/optical-control-of-dopamine-receptors-using-a-photoswitchable-tethered-inverse-agonist
#2
Prashant Donthamsetti, Nils Winter, Matthias Schönberger, Joshua Levitz, Cherise Stanley, Jonathan A Javitch, Ehud Y Isacoff, Dirk Trauner
Family A G protein-coupled receptors (GPCRs) control diverse biological processes and are of great clinical relevance. Their archetype rhodopsin becomes naturally light sensitive by binding covalently to the photoswitchable tethered ligand (PTL) retinal. Other GPCRs, however, neither bind covalently to ligands nor are light sensitive. We sought to impart the logic of rhodopsin to light-insensitive Family A GPCRs in order to enable their remote control in a receptor-specific, cell-type-specific and spatio-temporally precise manner...
November 22, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29166086/focused-conformational-sampling-in-proteins
#3
Marco Bacci, Cassiano Langini, Jiří Vymětal, Amedeo Caflisch, Andreas Vitalis
A detailed understanding of the conformational dynamics of biological molecules is difficult to obtain by experimental techniques due to resolution limitations in both time and space. Computer simulations avoid these in theory but are often too short to sample rare events reliably. Here we show that the progress index-guided sampling (PIGS) protocol can be used to enhance the sampling of rare events in selected parts of biomolecules without perturbing the remainder of the system. The method is very easy to use as it only requires as essential input a set of several features representing the parts of interest sufficiently...
November 21, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29166022/dynamics-of-ompf-trimer-formation-in-the-bacterial-outer-membrane-of-escherichia-coli
#4
Huilin Ma, Aliza Khan, Shikha Nangia
The self-assembly of outer membrane protein F (OmpF) in the outer membrane of Escherichia coli Gram-negative bacteria was studied using multiscale molecular dynamics simulations. To facilitate the long timescale required for protein assembly, coarse-grained parameterization of E. coli outer membrane lipids was first developed. The OmpF monomers formed stable dimers at specific protein-protein interactions sites irrespective of the lipid membrane environment. The dimer intermediate was asymmetric but provided a template to form a symmetric trimer...
November 22, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
https://www.readbyqxmd.com/read/29166011/a-cooperative-folding-unit-as-the-structural-link-for-energetic-coupling-within-a-protein
#5
Nathan W Gardner, Sarah M McGinness, Jainik Panchal, Elizabeth M Topp, Chiwook Park
Previously, we demonstrated that ligand binding to Escherichia coli cofactor-dependent phosphoglycerate mutase (dPGM), a homodimeric protein, is energetically coupled with dimerization. The equilibrium unfolding of dPGM occurs with a stable, monomeric intermediate. Binding of several non-substrate metabolites stabilizes the dimeric native form over the monomeric intermediate, reducing the population of the intermediate. Both the active site and the dimer interface appear to be unfolded in the intermediate. We hypothesized that a loop containing residues 118-152 was responsible for the energetic coupling between the dimer interface and the distal active site and was unfolded in the intermediate...
November 22, 2017: Biochemistry
https://www.readbyqxmd.com/read/29165861/engineered-biomolecular-recognition-of-rdx-using-a-thermostable-alcohol-dehydrogenase-as-a-protein-scaffold
#6
Beyza Bulutoglu, Jennifer Haghpanah, Elliot Campbell, Scott A Banta
There are many biotechnology applications that would benefit from simple, stable proteins with engineered biomolecular recognition. Here we explored the hypothesis that a thermostable alcohol dehydrogenase (AdhD from P. furisosus) could be engineered to bind a small molecule instead of a cofactor or molecules involved in the catalytic transition state. We chose the explosive molecule 1,3,5-trinitro-1,3,5-triazine (RDX) as a proof-of-concept. Its low solubility in water was exploited for immobilization for biopanning using ribosome display...
November 22, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29165759/transient-receptor-potential-melastatin-4-cation-channel-in-pediatric-heart-block
#7
J Tian, X-J An, M-Y Fu
Progressive cardiac conduction disease (PCCD) is a common pediatric heart conduction disorder. It is an autosomal inheritance of rare mutations, which leads to familial cases of PCCD. In these cases, the His-Purkinje system's conductive capacity is progressively deranged, involving either right or left bundle branch block. Also, QRS complexes display widening is an important characteristic that culminates in complete AV block, syncope, and sudden death. Mutations in TRPM4 gene that encodes for transient receptor potential melastatin 4 have recently been reported to cause familial cases of PCCD and heart block...
October 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29165690/the-regulatory-g4-motif-of-the-kirsten-ras-kras-gene-is-sensitive-to-guanine-oxidation-implications-on-transcription
#8
Susanna Cogoi, Annalisa Ferino, Giulia Miglietta, Erik B Pedersen, Luigi E Xodo
KRAS is one of the most mutated genes in human cancer. It is controlled by a G4 motif located upstream of the transcription start site. In this paper, we demonstrate that 8-oxoguanine (8-oxoG), being more abundant in G4 than in non-G4 regions, is a new player in the regulation of this oncogene. We designed oligonucleotides mimicking the KRAS G4-motif and found that 8-oxoG impacts folding and stability of the G-quadruplex. Dimethylsulphate-footprinting showed that the G-run carrying 8-oxoG is excluded from the G-tetrads and replaced by a redundant G-run in the KRAS G4-motif...
November 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29165680/a-thermus-phage-protein-inhibits-host-rna-polymerase-by-preventing-template-dna-strand-loading-during-open-promoter-complex-formation
#9
Wei-Yang Ooi, Yuko Murayama, Vladimir Mekler, Leonid Minakhin, Konstantin Severinov, Shigeyuki Yokoyama, Shun-Ichi Sekine
RNA polymerase (RNAP) is a major target of gene regulation. Thermus thermophilus bacteriophage P23-45 encodes two RNAP binding proteins, gp39 and gp76, which shut off host gene transcription while allowing orderly transcription of phage genes. We previously reported the structure of the T. thermophilus RNAP•σA holoenzyme complexed with gp39. Here, we solved the structure of the RNAP•σA holoenzyme bound with both gp39 and gp76, which revealed an unprecedented inhibition mechanism by gp76. The acidic protein gp76 binds within the RNAP cleft and occupies the path of the template DNA strand at positions -11 to -4, relative to the transcription start site at +1...
November 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29165665/novel-structural-features-drive-dna-binding-properties-of-cmr-a-crp-family-protein-in-tb-complex-mycobacteria
#10
Sridevi Ranganathan, Jonah Cheung, Michael Cassidy, Christopher Ginter, Janice D Pata, Kathleen A McDonough
Mycobacterium tuberculosis (Mtb) encodes two CRP/FNR family transcription factors (TF) that contribute to virulence, Cmr (Rv1675c) and CRPMt (Rv3676). Prior studies identified distinct chromosomal binding profiles for each TF despite their recognizing overlapping DNA motifs. The present study shows that Cmr binding specificity is determined by discriminator nucleotides at motif positions 4 and 13. X-ray crystallography and targeted mutational analyses identified an arginine-rich loop that expands Cmr's DNA interactions beyond the classical helix-turn-helix contacts common to all CRP/FNR family members and facilitates binding to imperfect DNA sequences...
November 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29165639/human-cancer-tissues-exhibit-reduced-a-to-i-editing-of-mirnas-coupled-with-elevated-editing-of-their-targets
#11
Yishay Pinto, Ilana Buchumenski, Erez Y Levanon, Eli Eisenberg
A-to-I RNA editing is an important post-transcriptional modification, known to be altered in tumors. It targets dozens of sites within miRNAs, some of which impact miRNA biogenesis and function, as well as many miRNA recognition sites. However, the full extent of the effect of editing on regulation by miRNAs and its behavior in human cancers is still unknown. Here we systematically characterized miRNA editing in 10 593 human samples across 32 cancer types and normal controls. We find that the majority of previously reported sites show little to no evidence for editing in this dataset, compile a list of 58 reliable miRNA editing sites, and study them across normal and cancer samples...
November 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29165618/human-specific-mutations-and-positively-selected-sites-in-marco-confer-functional-changes
#12
Kyle E Novakowski, Nicholas V L Yap, Charles Yin, Kaori Sakamoto, Bryan Heit, G Brian Golding, Dawn M E Bowdish
Macrophage Receptor with COllagenous structure (MARCO) is a class A scavenger receptor that binds, phagocytoses, and modifies inflammatory responses to bacterial pathogens. Multiple candidate gene approach studies have shown that polymorphisms in MARCO are associated with susceptibility or resistance to Mycobacterium tuberculosis infection, but how these variants alter function is not known. To complement candidate gene approach studies, we previously used phylogenetic analyses to identify a residue, glutamine 452 (Q452), within the ligand-binding Scavenger Receptor Cysteine Rich (SRCR) domain as undergoing positive selection in humans...
November 20, 2017: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/29165589/ns3-helicase-from-dengue-virus-specifically-recognizes-viral-rna-sequence-to-ensure-optimal-replication
#13
Crystall M D Swarbrick, Chandrakala Basavannacharya, Kitti W K Chan, Shu-Ann Chan, Daljit Singh, Na Wei, Wint Wint Phoo, Dahai Luo, Julien Lescar, Subhash G Vasudevan
The protein-RNA interactions within the flavivirus replication complex (RC) are not fully understood. Our structure of dengue virus NS3 adenosine triphosphatase (ATPase)/helicase bound to the conserved 5' genomic RNA 5'-AGUUGUUAGUCU-3' reveals that D290 and R538 make specific interactions with G2 and G5 bases respectively. We show that single-stranded 12-mer RNA stimulates ATPase activity of NS3, however the presence of G2 and G5 leads to significantly higher activation. D290 is adjacent to the DEXH motif found in SF2 helicases like NS3 and interacts with R387, forming a molecular switch that activates the ATPase site upon RNA binding...
November 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29165449/short-two-armed-lanthanide-binding-tags-for-paramagnetic-nmr-spectroscopy-based-on-chiral-1-4-7-10-tetrakis-2-hydroxypropyl-1-4-7-10-tetraazacyclododecane-scaffolds
#14
Michael D Lee, Matthew L Dennis, Bim Graham, James D Swarbrick
A new pair of enantiomeric two-armed lanthanide-binding tags have been developed for paramagnetic NMR studies of proteins. The tags produce large and significantly different paramagnetic effects to one another when bound to the same tagging site. Additionally, they are less sensitive to sample pH than our previous two-armed tag designs.
November 22, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29165246/regulatory-coiled-coil-domains-promote-head-to-head-assemblies-of-aaa-chaperones-essential-for-tunable-activity-control
#15
Marta Carroni, Kamila B Franke, Michael Maurer, Jasmin Jäger, Ingo Hantke, Felix Gloge, Daniela Linder, Sebastian Gremer, Kürşad Turgay, Bernd Bukau, Axel Mogk
Ring-forming AAA+ chaperones exert ATP-fueled substrate unfolding by threading through a central pore. This activity is potentially harmful requiring mechanisms for tight repression and substrate-specific activation. The AAA+ chaperone ClpC with the peptidase ClpP forms a bacterial protease essential to virulence and stress resistance. The adaptor MecA activates ClpC by targeting substrates and stimulating ClpC ATPase activity. We show how ClpC is repressed in its ground state by determining ClpC cryo-EM structures with and without MecA...
November 22, 2017: ELife
https://www.readbyqxmd.com/read/29165116/circular-rna-profiles-in-mouse-lung-tissue-induced-by-radon
#16
Weiwei Pei, Lijing Tao, Leshuai W Zhang, Shuyu Zhang, Jianping Cao, Yang Jiao, Jian Tong, Jihua Nie
BACKGROUND: Radon is a known human lung carcinogen, whose underlying carcinogenic mechanism remains unclear. Recently, circular RNA (circRNA), a class of endogenous non-protein coding RNAs that contain a circular loop, was found to exhibit multiple biological effects. In this study, circRNA profiles in mouse lung tissues between control and radon exposure were analyzed. METHODS: Six mice were exposed to radon at concentration of 100,000 Bq/m(3), 12 h/d, for up to cumulative doses of 60 working level months (WLM)...
April 7, 2017: Environmental Health and Preventive Medicine
https://www.readbyqxmd.com/read/29164996/cptp-a-sphingolipid-transfer-protein-that-regulates-autophagy-and-inflammasome-activation
#17
Shrawan Kumar Mishra, Yong-Guang Gao, Yibin Deng, Charles E Chalfant, Edward H Hinchcliffe, Rhoderick E Brown
The macroautophagy/autophagy and inflammasome pathways are linked through their roles in innate immunity and chronic inflammatory disease. Ceramide-1-phosphate (C1P) is a bioactive sphingolipid that regulates pro-inflammatory eicosanoid production. Whether C1P also regulates autophagy and inflammasome assembly/activation is not known. Here we show that CPTP (a protein that traffics C1P from its site of phosphorylation in the trans-Golgi to target membranes) regulates both autophagy and inflammasome activation...
November 22, 2017: Autophagy
https://www.readbyqxmd.com/read/29164827/inhibitors-against-fungal-cell-wall-remodelling-enzymes
#18
Pedro Merino, Ignacio Delso, Jessika Valero-Gonzalez, Fernando Gomollon-Bel, Jorge Castro-Lopez, Wenxia Fang, Iva Navratilova, Daan M F van Aalten, Tomas Tejero, Ramon Hurtado-Guerrero
Fungal beta-1,3-glucan glucanosyltransferases are glucan-remodeling enzymes that play important roles in cell wall integrity, and are essential for the viability of pathogenic fungi/yeasts. As such, they are considered possible drug targets, although inhibitors of this class of enzymes have not yet been reported. Here, we report a multidisciplinary approach, based on a structure-guided design using a highly conserved transglycosylase from Sacharomyces cerevisiae, that leads to carbohydrate derivatives with high affinity for Aspergillus fumigatus Gel4...
November 22, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29164779/characterization-of-the-interaction-forces-in-a-drug-carrier-complex-of-doxorubicin-with-a-drug-binding-peptide
#19
Gergana Gocheva, Nina Ilieva, Kalina Peneva, Anela Ivanova
Polypeptide-based materials are used as building blocks for drug delivery systems aimed at toxicity decrease of chemotherapeutics. A molecular-level approach is adopted for investigating the non-covalent interactions between doxorubicin and a recently synthesized drug-binging peptide as a key part of a system for delivery to neoplastic cells. MD simulations in aqueous solution at room and body temperature are applied to investigate the structure and the binding modes within the drug-peptide complex. The tryptophans are outlined as the main chemotherapeutic adsorption sites and the importance of their placement in the peptide sequence is highlighted...
November 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29164729/identification-and-characterization-of-a-histamine-binding-lipocalin-like-molecule-from-the-relapsing-fever-tick-ornithodoros-turicata
#20
G Neelakanta, H Sultana, D E Sonenshine, J F Andersen
Lipocalins are low molecular weight membrane transporters that are abundantly expressed in the salivary glands and other tissues of ticks. In this study, we identified a lipocalin-like molecule, designated as otlip, from the soft ticks Ornithodoros turicata, the vector for the relapsing fever causing spirochete Borrelia turicatae. We noted that the expression of otlip was developmentally regulated, with adult ticks expressing significantly higher levels in comparison to the larvae or nymphal ticks. Expression of otlip was evident in both fed and unfed O...
November 22, 2017: Insect Molecular Biology
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