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acid pocket

Ashley Best, Christopher Price, Mateja Ozanic, Marina Santic, Snake Jones, Yousef Abu Kwaik
Legionella pneumophila invades protozoa with an "accidental" ability to cause pneumonia upon transmission to humans. To support its nutrition during intracellular residence, L. pneumophila relies on host amino acids as the main source of carbon and energy to feed the TCA cycle. Despite the apparent lack of a requirement for glucose for L. pneumophila growth in vitro and intracellularly, the organism contains multiple amylases, which hydrolyze polysaccharides into glucose monomers. Here we describe one predicted putative amylase, LamB, which is uniquely present only in L...
April 20, 2018: Scientific Reports
Karel Mena-Ulecia, Desmond MacLeod-Carey
2-phenyl-benzotriazole xenobiotic compounds (PBTA-4, PBTA-6, PBTA-7 and PBTA-8) that were previously isolated and identified in waters of the Yodo river, in Japan (Nukaya et al., 2001; Ohe et al., 2004; Watanabe et al., 2001) were characterized as powerful pro-mutagens. In order to predict the activation mechanism of these pro-mutagens, we designed a computational biochemistry protocol, which includes, docking experiments, molecular dynamics simulations and free energy decomposition calculations to obtain information about the interaction of 2-phenyl-benzotriazole molecules into the active center of cytochrome P450-CYP1A1 (CYP1A1)...
April 7, 2018: Computational Biology and Chemistry
António Martins, Thorsten Pfirrmann, Stijn Heessen, Gustav Sundqvist, Vincent Bulone, Claes Andréasson, Per O Ljungdahl
Ssy5 is a signaling endoprotease that plays a key role in regulating central metabolism, cellular aging, and morphological transitions important for growth and survival of yeast (Saccharomyces cerevisiae) cells. In response to extracellular amino acids, Ssy5 proteolytically activates the transcription factors Stp1 and Stp2, leading to enhanced Ssy1-Ptr3-Ssy5 (SPS3) sensor-regulated gene expression. Ssy5 comprises a catalytic (Cat) domain and an extensive regulatory prodomain. However, Ssy5 is refractory to both broad-spectrum and serine protease-specific inhibitors, confounding its classification as a serine protease, and no information about Ssy5's cleavage-site preferences and its mechanism of substrate selection is available...
April 16, 2018: Journal of Biological Chemistry
Seong W Kang, Srinivas Jayanthi, Gurueswar Nagarajan, Thallapuranam Krishnaswamy Suresh Kumar, Wayne J Kuenzel
Vasotocin 1a and 1b receptors (V1aR and V1bR) have been shown to play important roles in the neuroendocrine regulation of stress responses via the anterior pituitary (AP) of birds. To identify effective subtype-specific antagonists for the chicken V1aR (cV1aR) and cV1bR, potential antagonists to the mammalian V1R were screened against the cV1aR and cV1bR 3D structural models by molecular docking analysis with determination of binding pocket / amino acid residues involved in the interaction. The antagonistic effects of the selected ligands were examined by measuring pro-opiomelanocortin (POMC) heteronuclear RNA (hnPOMC) levels following the in vitro stress administration to primary chicken AP cells...
April 16, 2018: Journal of Biomolecular Structure & Dynamics
T Das, I Alabi, M Colley, F Yan, W Griffith, S Bach, S T Weintraub, R Renthal
Proteins in the venom of the fire ant Solenopsis invicta have been suggested to function in pheromone binding. Venom from queens and workers contains different isoforms of these proteins, consistent with the differing pheromones they secrete, but questions remain about the venom protein composition and glandular source. We found that the queen venom contains a previously uncharacterized pheromone-binding protein paralogue known as Sol i 2X1. Using imaging mass spectrometry, we located the main venom proteins in the poison sac, implying that pheromones might have to compete with venom alkaloids for binding...
April 15, 2018: Insect Molecular Biology
Emmanuel A Adeniji, Fisayo A Olotu, Mahmoud E S Soliman
Liver mitochondrial aldehyde dehydrogenase 2 (ALDH2) enzyme is responsible for the rapid conversion of acetaldehyde to acetic acid. ALDH2 (E487K) polymorphism results in an inactive allele (ALDH2*2) which cause dysfunctional acetaldehyde metabolism. The 3D structure of an enzyme is crucial to its functionality and a disruption in its structural integrity could result in its metabolic inefficiency and dysfunctionality. Allosteric targeting of polymorphs could facilitate the restoration of wildtype functionalities in ALDH2 polymorphs and serve as an advancement in the treatment of associated diseases...
April 12, 2018: Protein Journal
Kyungjin Min, Hye-Jin Yoon, Atsushi Matsuura, Yong Hwan Kim, Hyung Ho Lee
L-pipecolic acid is a non-protein amino acid commonly found in plants, animals, and microorganisms. It is a well-known precursor to numerous microbial secondary metabolites and pharmaceuticals, including anticancer agents, immunosuppressants, and several antibiotics. Lysine cyclodeaminase (LCD) catalyzes β-deamination of L-lysine into L-pipecolic acid using β-nicotinamide adenine dinucleotide as a cofactor. Expression of a human homolog of LCD, μ-crystallin, is elevated in prostate cancer patients. To understand the structural features and catalytic mechanisms of LCD, we determined the crystal structures of Streptomyces pristinaespiralis LCD (SpLCD) in (i) a binary complex with NAD+, (ii) a ternary complex with NAD+ and L-pipecolic acid, (iii) a ternary complex with NAD+ and L-proline, and (iv) a ternary complex with NAD+ and L-2,4-diamino butyric acid...
April 5, 2018: Molecules and Cells
Xiao-Zheng Dou, Dinesh Nath, Younghwa Shin, Jian-Xing Ma, Adam S Duerfeldt
Small molecule agonism of PPARα represents a promising new avenue for the development of non-invasive treatments for oculovascular diseases like diabetic retinopathy and age-related macular degeneration. Herein we report initial structure-activity relationships for the newly identified quinoline-based PPARα agonist, Y-0452. Preliminary computational studies led to the hypothesis that carboxylic acid transposition and deconstruction of the Y-0452 quinoline system would enhance ligand-protein interactions and better complement the nature of the binding pocket...
April 5, 2018: Bioorganic & Medicinal Chemistry Letters
Yasmeen Yousif Ahmed Elyas, Kazusa Miyatani, Tomohiro Bito, Misugi Uraji, Tadashi Hatanaka, Katsuhiko Shimizu, Jiro Arima
d-Stereospecific amidohydrolase from Streptomyces sp. 82F2 (DAH) recognizes d-amino acyl ester derivatives as substrates and catalyzes hydrolysis and aminolysis to yield d-amino acids and d-amino acyl peptides or amide derivatives, respectively. Crystallographic analysis has revealed that DAH possesses a large cavity with a small pocket at the bottom. Because the pocket is close to the catalytic center and is thought to interact with substrates, we examined the function of the eight residues that form the pocket in terms of substrate recognition and aminolysis via mutational analysis...
April 5, 2018: Journal of Bioscience and Bioengineering
Lina Riegler-Berket, Andrea Leitmeier, Philipp Aschauer, Ingrid Dreveny, Monika Oberer
Monoacylglycerol lipases (MGL) are a subclass of lipases that predominantly hydrolyze monoacylglycerol into glycerol and free fatty acid. MGLs are ubiquitous enzymes across species and play a role in lipid metabolism, affecting energy homeostasis and signaling processes. Structurally, MGLs belong to the α/β hydrolase fold family with a cap covering the substrate binding pocket. Analysis of the known 3D structures of human, yeast and bacterial MGLs revealed striking similarity of the cap architecture. Since MGLs from different organisms share very low sequence similarity, it is difficult to identify MGLs based on the amino acid sequence alone...
April 5, 2018: Biochimica et Biophysica Acta
Carrie Hiser, Jian Liu, Shelagh Ferguson-Miller
Three mutant forms of Rhodobacter sphaeroides cytochrome c oxidase (RsCcO) were created to test for multiple K-path entry sites (E101W), the existence of an "upper ligand site" (M350 W), and the nature and binding specificity of the "lower ligand site" (P315W/E101A) in the region of a crystallographically-defined deoxycholate at the K-path entrance. The effects of inhibitory and stimulatory detergents (dodecyl maltoside and Tween20) on these mutants are presented, as well as competition with other ligands, including the potentially physiologically relevant ligands cholesterol and retinoic acid...
April 4, 2018: Biochimica et Biophysica Acta
Malin Silverå Ejneby, Xiongyu Wu, Nina E Ottosson, E Peter Münger, Ingemar Lundström, Peter Konradsson, Fredrik Elinder
Dehydroabietic acid (DHAA) is a naturally occurring component of pine resin that was recently shown to open voltage-gated potassium (KV ) channels. The hydrophobic part of DHAA anchors the compound near the channel's positively charged voltage sensor in a pocket between the channel and the lipid membrane. The negatively charged carboxyl group exerts an electrostatic effect on the channel's voltage sensor, leading to the channel opening. In this study, we show that the channel-opening effect increases as the length of the carboxyl-group stalk is extended until a critical length of three atoms is reached...
April 6, 2018: Journal of General Physiology
Katarína Furmanová, Jan Byška, Eduard M Gröller, Ivan Viola, Jan J Paleček, Barbora Kozlíková
BACKGROUND: Studying the patterns of protein-protein interactions (PPIs) is fundamental for understanding the structure and function of protein complexes. The exploration of the vast space of possible mutual configurations of interacting proteins and their contact zones is very time consuming and requires the proteomic expert knowledge. RESULTS: In this paper, we propose a novel tool containing a set of visual abstraction techniques for the guided exploration of PPI configuration space...
April 6, 2018: BMC Bioinformatics
Dudley H McNitt, Soo Jeon Choi, Douglas R Keene, Livingston Van De Water, Flavia Squeglia, Rita Berisio, Slawomir Lukomski
Keratinized epidermis constitutes a powerful barrier of the mucosa and skin, effectively preventing bacterial invasion, unless it is wounded and no longer protective. Wound healing involves deposition of distinct extracellular matrix (ECM) proteins enriched in cellular fibronectin (cFn) isoforms containing extra domain A (EDA). The streptococcal collagen-like protein 1 (Scl1) is a surface adhesin of group A Streptococcus (GAS), which contains an N-terminal variable (V) domain and a C-terminally located collagen-like domain...
April 2, 2018: Journal of Biological Chemistry
Kyla A Britson, Stephanie Y Yang, Thomas E Lloyd
PURPOSE OF REVIEW: Our goal is to review the recent literature pertaining to the genetics of sporadic inclusion body myositis (IBM). RECENT FINDINGS: In a study of 252 IBM patients, the class II MHC allele HLA-DRB1*03:01 showed the most significant association with IBM, and that risk could be largely attributed to amino acids within the peptide-binding pocket. Candidate gene sequencing identified rare missense variants in proteins regulating protein homeostasis including VCP and SQSTM1...
April 2, 2018: Current Rheumatology Reports
Rameshwar U Kadam, Ian A Wilson
The influenza virus hemagglutinin (HA) glycoprotein mediates receptor binding and membrane fusion during viral entry in host cells. Blocking these key steps in viral infection has applications for development of novel antiinfluenza therapeutics as well as vaccines. However, the lack of structural information on how small molecules can gain a foothold in the small, shallow receptor-binding site (RBS) has hindered drug design against this important target on the viral pathogen. Here, we report on the serendipitous crystallization-based discovery of a small-molecule N -cyclohexyltaurine, commonly known as the buffering agent CHES, that is able to bind to both group-1 and group-2 HAs of influenza A viruses...
April 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
Sajjad Ahmad, Saad Raza, Asma Abro, Klaus R Liedl, Syed Sikander Azam
KdsB (3-deoxy-manno-octulosonate cytidylyltransferase) is a highly specific and selective bacterial enzyme that catalyzes KDO (3-Deoxy-D-mano-oct-2-ulosonic acid) activation in KDO biosynthesis pathway. Failure in KDO biosynthesis causes accumulation of lipid A in the bacterial outer membrane that leads to cell growth arrest. This study reports a combinatorial approach comprising virtual screening of natural drugs library, molecular docking, computational pharmacokinetics, molecular dynamics simulation, and binding free energy calculations for the identification of potent lead compounds against the said enzyme...
March 31, 2018: Journal of Biomolecular Structure & Dynamics
Linkui Zhang, Ying Zhao, Jian Wang, Donglin Yang, Chenwen Zhao, Changli Wang, Chao Ma, Maosheng Cheng
Diverse of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed, synthesized and evaluated for their neuroprotective activity against NMDA-induced cytotoxicity in vitro, and 5q exhibited excellent neuroprotective activity. The compound 5q was selected for further investigation. We found that 5q could attenuate Ca2+ influx induced by NMDA, meanwhile, 5q could suppress the NR2B up-regulation and increase p-ERK1/2 expression. The molecular docking results showed that 5q might fit well in the binding pocket of 4 and interact with some key residues in the binding pocket of 1 simultaneously...
March 23, 2018: European Journal of Medicinal Chemistry
Zhe Xu, Ting Cai, Neng Xiong, Shu-Ping Zou, Ya-Ping Xue, Yu-Guo Zheng
Nitrilases can hydrolyze nitriles to corresponding carboxylic acids in one single step, which have great potential as valuable biocatalysts for chemical synthesis. However, the poor thermostability of the nitrilases restrict their applications in industry. In this work, error-prone PCR and site-directed mutagenesis were utilized to improve the thermostability of nitrilases. Several mutants (AcN-Q339K, AcN-Q343K, AcN-T201F, AcN-T201W, AcN-T201L, AcN-T201I) were obtained with dramatically improved thermostability...
June 2018: Enzyme and Microbial Technology
Amit Lather, Anurag Khatkar, Sunil Sharma
BACKGROUND: Infections caused by microorganisms are the major cause of death today. The tremendous and improper use of antimicrobial agents leads to antimicrobial resistance. AIM AND OBJECTIVE: Various currently available antimicrobial drugs are inadequate to control the infections and lead to various adverse drug reactions. Efforts based on computer-aided drug design (CADD) can excavate a large number of databases to generate new, potent hits and minimize the requirement of time as well as money for the discovery of newer antimicrobials...
March 29, 2018: Combinatorial Chemistry & High Throughput Screening
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