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Protein Crystal Structure

Wint Wint Phoo, Zhenzhen Zhang, Melissa Wirawan, Edwin Chew Jun Chen, Chew Bing Liang Alvin, Jenny Kouretova, Torsten Steinmetzer, Dahai Luo
Zika virus NS2B-NS3 protease plays an essential role in viral replication by processing the viral polyprotein into individual proteins. The viral protease is therefore considered as an ideal antiviral drug target. To facilitate the development of protease inhibitors, we report three high-resolution co-crystal structures of bZiPro with peptidomimetic inhibitors composed of a P1-P4 segment and different P1' residues. Compounds 1 and 2 possess small P1' groups that are cleaved by bZiPro, which could be detected by mass spectrometry...
October 10, 2018: Antiviral Research
Ragnhild Bager Skjerning, Meriem Senissar, Kristoffer Winther, Kenn Gerdes, Ditlev E Brodersen
Type II toxin-antitoxin (TA) modules, which are important cellular regulators in prokaryotes, usually encode two proteins, a toxin that inhibits cell growth and a non-toxic and labile inhibitor (antitoxin) that binds to and neutralizes the toxin. Here, we demonstrate that the res-xre locus from Photorhabdus luminescens and other bacterial species function as bona fide TA modules in E. coli. The 2.2 Å crystal structure of the intact Pseudomonas putida RES-Xre TA complex reveals an unusual 2:4 stoichiometry in which a central RES toxin dimer binds two Xre antitoxin dimers...
October 13, 2018: Molecular Microbiology
Ashley M Sherp, Soon Goo Lee, Evelyn Schraft, Joseph M Jez
Herbicide-resistance traits are the most widely used agriculture biotechnology products. Yet, to maintain their effectiveness and to mitigate selection of herbicide-resistant weeds, the discovery of new resistance traits that use different chemical modes of action is essential. In plants, the Gretchen Hagen 3 (GH3) acyl acid amido synthetases catalyze the conjugation of amino acids to jasmonate and auxin phytohormones. This reaction chemistry has not been explored as a possible approach for herbicide modification and inactivation...
October 12, 2018: Journal of Biological Chemistry
Thanuja Gangi Setty, Jonathan C Mowers, Aaron G Hobbs, Shubha P Maiya, Sanaa Syed, Robert S Munson, Michael A Apicella, Ramaswamy Subramanian
The primary role of bacterial periplasmic binding proteins is sequestration of essential metabolites present at a low concentration in the periplasm and making them available for active transporters that transfer these ligands into the bacterial cell. The periplasmic binding proteins(SiaP) from the tripartite ATP-independent periplasmic (TRAP) transport system that transports mammalian host-derived sialic acids, have been well studied from different pathogenic bacteria, including Haemophilus influenzae , Fusobacterium nucleatum , Pasteurella multocida , and Vibrio cholerae SiaPs bind the sialic acid N-acetylneuraminic acid (Neu5Ac) with nanomolar affinity by forming electrostatic and hydrogen bonding interactions...
October 12, 2018: Journal of Biological Chemistry
Francisco Del Caño-Ochoa, Araceli Grande-García, María Reverte-López, Marco D'Abramo, Santiago Ramón-Maiques
The dihydroorotase (DHOase) domain of the multifunctional protein carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) catalyzes the third step in the de novo biosynthesis of pyrimidine nucleotides in animals. The crystal structure of the DHOase domain of human CAD (huDHOase) revealed that, despite evolutionary divergence, its active site components are highly conserved with those in bacterial DHOases, encoded as monofunctional enzymes. An important element for catalysis, conserved from Escherichia coli to humans, is a flexible loop that closes as a lid over the active site...
October 12, 2018: Journal of Biological Chemistry
Alketa Tarushi, George D Geromichalos, Dimitris P Kessissoglou, George Psomas
The in vitro and in silico biological properties of two manganese complexes with the non-steroidal anti-inflammatory drug mefenamic acid (Hmef) in the presence or absence of salicylaldoxime (Η2 sao), i.e. [Μn6 (O)2 (mef)2 (sao)6 (CH3 OH)4 ] 1, and [Μn(mef)2 (CH3 OH)4 ] 2, respectively, are presented in the present contribution. More specifically, the in vitro biological activity of the complexes was investigated by studying their affinity to calf-thymus DNA (by diverse spectroscopic and physicochemical techniques) and their binding towards bovine (BSA) or human serum albumin (HSA) (by fluorescence emission spectroscopy)...
September 29, 2018: Journal of Inorganic Biochemistry
Amandeep Singh, Sheikh Mohammad Arif, Pau Biak Sang, Umesh Varshney, M Vijayan
Mis-incorporation of modified nucleotides, such as 5-methyl-dCTP or 8-oxo-dGTP, in DNA can be detrimental to genomic integrity. MutT proteins are sanitization enzymes which function by hydrolyzing such nucleotides and regulating the pool of free nucleotides in the cytoplasm. Mycobacterial genomes have a set of four MutT homologs, namely, MutT1, MutT2, MutT3 and MutT4. Mycobacterial MutT2 hydrolyzes 5m-dCTP and 8-oxo-dGTP to their respective monophosphate products. Additionally, it can hydrolyze canonical nucleotides dCTP and CTP, with a suggested role in sustaining their optimal levels in the nucleotide pool...
October 9, 2018: Journal of Structural Biology
Shiteshu Shrimal, Reid Gilmore
Asparagine-linked (N-linked) glycosylation is one of the most common protein modification reactions in eukaryotic cells, occurring upon the majority of proteins that enter the secretory pathway. X-ray crystal structures of the single subunit OSTs from eubacterial and archaebacterial organisms revealed the location of donor and acceptor substrate binding sites and provided the basis for a catalytic mechanism. Cryoelectron microscopy structures of the octameric yeast OST provided substantial insight into the organization and assembly of the multisubunit oligosaccharyltransferases...
October 11, 2018: Glycobiology
William A Cramer
Structure-function studies of the cytochrome b6 f complex, the central hetero-oligomeric membrane protein complex in the electron transport chain of oxygenic photosynthesis, which formed the basis for a high-resolution (2.5 Å) crystallographic solution of the complex, are described. Structure-function differences between the structure of subunits of the bc complexes, b6 f, and bc1 from mitochondria and photosynthetic bacteria, which are often assumed to function identically, are discussed. Major differences which suggest that quinone-dependent electron transport pathways can vary in b6 f and bc1 complexes are as follows: (a) an additional c-type heme, cn , and bound single copies of chlorophyll a and β-carotene in the b6 f complex; and (b) a cyclic electron transport pathway that encompasses the b6 f and PSI reaction center complexes...
October 11, 2018: Photosynthesis Research
Azzurra Carlon, Enrico Ravera, Giacomo Parigi, Garib N Murshudov, Claudio Luchinat
Data integration in structural biology has become a paradigm for the characterization of biomolecular systems, and it is now accepted that combining different techniques can fill the gaps in each other's blind spots. In this frame, one of the combinations, which we have implemented in REFMAC-NMR, is residual dipolar couplings from NMR together with experimental data from X-ray diffraction. The first are exquisitely sensitive to the local details but does not give any information about overall shape, whereas the latter encodes more the information about the overall shape but at the same time tends to miss the local details even at the highest resolutions...
October 11, 2018: Journal of Biomolecular NMR
Raymond Pratt, Garry J Handelman, Thomas E Edwards, Ajay Gupta
There are several options available for intravenous application of iron supplements, but they all have a similar structure:-an iron core surrounded by a carbohydrate coating. These nanoparticles require processing by the reticuloendothelial system to release iron, which is subsequently picked up by the iron-binding protein transferrin and distributed throughout the body, with most of the iron supplied to the bone marrow. This process risks exposing cells and tissues to free iron, which is potentially toxic due to its high redox activity...
October 11, 2018: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
Yan Fang, Jie Li, Pei-Pei Han, Qiu-Xia Han, Ming-Xue Li
Four metal complexes based on 2-benzoylpyridine N , N -dimethylthiosemicarbazone (Bp44mT) were designed. Free ligand and zinc(ii), diorganotin(iv), gallium(iii) and cadmium(ii) complexes all demonstrated pronounced activity, which was indicated using the growth inhibition test in vitro . Interestingly, most of the compounds were found to be selective against hepatocellular carcinoma (HepG2) cells but had little effect on normal hepatocyte (QSG7701) cells. In particular, Zn(Bp44mT)2 ( 1 ) exhibited toxicity on QSG7701 cells which approximately 12-fold lower than that on HepG2 cells...
September 1, 2018: Toxicology Research
H C Stephen Chan, Jingjing Wang, Krzysztof Palczewski, Slawomir Filipek, Horst Vogel, Zhi-Jie Liu, Shuguang Yuan
Identifying a target ligand binding site is an important step for structure-based rational drug design as shown here for G protein-coupled receptors (GPCRs), which are among the most popular drug targets. We applied long-time scale molecular dynamics simulations, coupled with mutagenesis studies, to two prototypical GPCRs, the M3 and M4 muscarinic acetylcholine receptors. Our results indicate that unlike synthetic antagonists, which bind to the classic orthosteric site, the endogenous agonist acetylcholine is able to diffuse into a much deeper binding pocket...
August 21, 2018: Chemical Science
Pingyuan Wang, Jia Zhou
Great success has been achieved in small molecule drug discovery programs, making extraordinary contributions for human health, especially in targeted therapy. Taking anticancer drug discovery as an example, small molecules traditionally inhibit the target protein enzyme activities and induce cancer cell apoptosis through the target binding. However, the target protein within tumor cells often recovers its activities, leading to acquired drug-resistance through the overexpression of the target protein or the generation of new mutations in the target protein [1]...
October 9, 2018: Current Topics in Medicinal Chemistry
Weiwei Xue, Tingting Fu, Guoxun Zheng, Gao Tu, Yang Zhang, Fengyuan Yang, Lin Tao, Lixia Yao, Feng Zhu
BACKGROUND: The human monoamine transporters (hMATs) primary including hSERT, hNET and hDAT are important targets for the treatment of depression and other behavioral disorders with more than availability of 30 approved drugs. OBJECTIVE: This paper is to review the recent progress in the binding mode and inhibitory mechanism of hMATs inhibitors with the central or allosteric binding sites, for the benefit of future hMATs inhibitor design and discovery. The structure-activity relationship (SAR) and the selectivity for hit/lead compounds to hMATs that evaluated by in vitro and in vivo experiments will be highlighted...
October 9, 2018: Current Medicinal Chemistry
Suruchi Singh, Ritesh Rajesh Sevalkar, Dibyendu Sarkar, Subramanian Karthikeyan
The gene Rv1828 in Mycobacterium tuberculosis is shown to be essential for the pathogen and encodes for an uncharacterized protein. In this study, we have carried out biochemical and structural characterization of Rv1828 at the molecular level to understand its mechanism of action. The Rv1828 is annotated as HTH-type MerR family transcription regulator based on its N-terminal amino acid sequence similarity. The MerR family protein binds to a specific DNA sequence in the spacer region between -35 and -10 elements of a promoter through its N-terminal domain and acts as transcriptional repressor or activator depending on the absence or presence of effector that binds to its C-terminal domain...
October 10, 2018: FEBS Journal
Hannia Liliana Almonacid-Mendoza, María Victoria Humbert, Aiste Dijokaite, David W Cleary, Yiwen Soo, Miao-Chiu Hung, Christian M Orr, Moritz M Machelett, Ivo Tews, Myron Christodoulides
Neisseria gonorrhoeae (gonococcus [Ng]) is the causative organism of the sexually transmitted disease gonorrhoea, and no effective vaccine exists currently. In this study, the structure, biological properties, and vaccine potential of the Ng-adhesin complex protein (Ng-ACP) are presented. The crystal structure of recombinant Ng-ACP (rNg-ACP) protein was solved at 1.65 Å. Diversity and conservation of Ng-ACP were examined in different Neisseria species and gonococcal isolates ( database) in silico , and protein expression among 50 gonococcal strains in the Centers for Disease Control and Prevention/Food and Drug Administration (CDCP/FDA) AR Isolate Bank was examined by Western blotting...
October 10, 2018: MSphere
Yuhong Wu, Jiang Zhu, Xiaolan Huang, Xia Zhou, Zhihua Du
Human Caprin-1 and Caprin-2 are prototypic members of the caprin (cytoplasmic activation/proliferation-associated protein) protein family. Vertebrate caprin proteins contain two highly conserved homologous regions (HR1 and HR2) and C-terminal RGG motifs. Drosophila caprin (dCaprin) shares HR1 and RGG motifs but lacks HR2. Caprin-1 and Caprin-2 have important and non-redundant functions. The detailed molecular mechanism s of their actions remain largely unknown. Previously, we determined the crystal structure of a ∼120-residue fragment of Caprin-1 within the HR1 region...
October 11, 2018: Journal of Biomolecular Structure & Dynamics
Ann-Sofie Jemth, Robert Gustafsson, Lars Bräutigam, Linda Henriksson, Karl S A Vallin, Antonio Sarno, Ingrid Almlöf, Evert Homan, Azita Rasti, Ulrika Warpman Berglund, Pål Stenmark, Thomas Helleday
Nucleotides in the free pool are more susceptible to nonenzymatic methylation than those protected in the DNA double helix. Methylated nucleotides like O6-methyl-dGTP can be mutagenic and toxic if incorporated into DNA. Removal of methylated nucleotides from the nucleotide pool may therefore be important to maintain genome integrity. We show that MutT homologue 1 (MTH1) efficiently catalyzes the hydrolysis of O6-methyl-dGTP with a catalytic efficiency similar to that for 8-oxo-dGTP. O6-methyl-dGTP activity is exclusive to MTH1 among human NUDIX proteins and conserved through evolution but not found in bacterial MutT...
October 10, 2018: Nucleic Acids Research
Alexei Gorelik, Ahmad Gebai, Katalin Illes, Daniele Piomelli, Bhushan Nagar
Palmitoylethanolamide is a bioactive lipid that strongly alleviates pain and inflammation in animal models and in humans. Its signaling activity is terminated through degradation by N -acylethanolamine acid amidase (NAAA), a cysteine hydrolase expressed at high levels in immune cells. Pharmacological inhibitors of NAAA activity exert profound analgesic and antiinflammatory effects in rodent models, pointing to this protein as a potential target for therapeutic drug discovery. To facilitate these efforts and to better understand the molecular mechanism of action of NAAA, we determined crystal structures of this enzyme in various activation states and in complex with several ligands, including both a covalent and a reversible inhibitor...
October 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
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