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https://www.readbyqxmd.com/read/27914062/computational-design-of-ligand-binding-proteins
#1
Christine E Tinberg, Sagar D Khare
The ability to design novel small-molecule binding sites in proteins is a stringent test of our understanding of the principles of molecular recognition, and would have many practical applications, in synthetic biology and medicine. Here, we describe a computational method in the context of the macromolecular modeling suite Rosetta to designing proteins with sites featuring predetermined interactions to ligands of choice. The required inputs for the method are a model of the small molecule and the desired interactions (e...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914004/hybrid-receptor-bound-mm-gbsa-per-residue-energy-based-pharmacophore-modelling-enhanced-approach-for-identification-of-selective-lta4h-inhibitors-as-potential-anti-inflammatory-drugs
#2
Patrick Appiah-Kubi, Mahmoud Soliman
Leukotriene A4 hydrolase has been identified as an enzyme with dual anti- and pro-inflammatory role, thus, the conversion of leukotriene to leukotriene B4 in the initiation stage of inflammation and the removal of the chemotactic Pro-Gly-Pro tripeptide. These findings make leukotriene A4 hydrolase an attractive drug target: suggesting an innovative approach towards the identification and design of novel class of compounds that can selectively inhibit leukotriene B4 synthesis while sparing the aminopeptidase activity...
December 2, 2016: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27911011/fragment-based-design-synthesis-and-biological-evaluation-of-1-substituted-indole-2-carboxylic-acids-as-selective-mcl-1-inhibitors
#3
Ziqian Wang, Wenjie Xu, Ting Song, Zongwei Guo, Lu Liu, Yudan Fan, Anhui Wang, Zhichao Zhang
Based on a known selective Mcl-1 inhibitor, 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid, we applied a fragment-based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl-1 over the Bcl-2 protein. After we deconstructed the 1H-indole-2-carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1-position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X-ray crystallography...
December 2, 2016: Archiv der Pharmazie
https://www.readbyqxmd.com/read/27908245/perfect-hemihedral-twinning-in-crystals-of-the-%C3%AE-subunit-of-translation-initiation-factor-2-from-sulfolobus-solfataricus-cause-and-effect
#4
O V Kravchenko, O S Nikonov, N A Nevskaya, E A Stolboushkina, V I Arkhipova, M B Garber, S V Nikonov
The crystal structure of the γ-subunit of translation initiation factor 2 from the archaeon Sulfolobus solfataricus (SsoIF2γ) has been solved based on perfectly hemihedral twinned data. The protein was cocrystallized with the 10-fold molar excess of GTP analog (GDPCP) over protein. However, no nucleotide was found in the structure, and the model demonstrated the apo form of the protein. Two slightly different molecules in the asymmetric unit of the crystal are related by the non-crystallographic 2-fold axis and form a tightly associated dimer...
October 2016: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/27907864/heterolytic-oo-bond-cleavage-functional-role-of-glu113-during-bis-fe-iv-formation-in-maug
#5
Jiafeng Geng, Lu Huo, Aimin Liu
The diheme enzyme MauG utilizes H2O2 to perform oxidative posttranslational modification on a protein substrate. A bis-Fe(IV) species of MauG was previously identified as a key intermediate in this reaction. Heterolytic cleavage of the OO bond of H2O2 drives the formation of the bis-Fe(IV) intermediate. In this work, we tested a hypothesis that a glutamate residue, Glu113 in the distal pocket of the pentacoordinate heme of MauG, facilitates heterolytic OO bond cleavage, thereby leading to bis-Fe(IV) formation...
November 9, 2016: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/27889632/synthesis-biological-evaluation-and-in-silico-molecular-modeling-of-pyrrolyl-benzohydrazide-derivatives-as-enoyl-acp-reductase-inhibitors
#6
Shrinivas D Joshi, Sheshagiri R Dixit, Venkatarao H Kulkarni, Christian Lherbet, Mallikarjuna N Nadagouda, Tejraj M Aminabhavi
In efforts to develop lead anti-TB compounds, a novel series of 19 pyrrolyl benzohydrazides were synthesized and screened to target enoyl-ACP reductase enzyme, which is one of the important enzymes involved in type II fatty acid biosynthetic pathway of M. tuberculosis. Pharmacophores were constructed using GALAHAD to generate alignment of data sets and calculated by Pareto ranking. The pharmacophore features were then filtered by Surflex-dock study using enoyl ACP reductase from M. tuberculosis. Compounds 5b and 5d showed H-bonding interactions with Tyr158, Thr196 and co-factor NAD(+) that fitted well within the binding pocket of InhA...
November 17, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27882315/septin-mutations-in-human-cancers
#7
REVIEW
Dimitrios Angelis, Elias T Spiliotis
Septins are GTP-binding proteins that are evolutionarily and structurally related to the RAS oncogenes. Septin expression levels are altered in many cancers and new advances point to how abnormal septin expression may contribute to the progression of cancer. In contrast to the RAS GTPases, which are frequently mutated and actively promote tumorigenesis, little is known about the occurrence and role of septin mutations in human cancers. Here, we review septin missense mutations that are currently in the Catalog of Somatic Mutations in Cancer (COSMIC) database...
2016: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/27881678/evolutionary-adaptation-of-the-essential-trna-methyltransferase-trmd-to-the-signaling-molecule-3-5-camp-in-bacteria
#8
Yong Zhang, Rym Agrebi, Lauren E Bellows, Jean-François Collet, Volkhard Kaever, Angelika Gründling
The nucleotide signaling molecule 3',5'-cyclic adenosine monophosphate (3',5'-cAMP) plays important physiological roles, ranging from carbon catabolite repression in bacteria to mediating the action of hormones in higher eukaryotes, including human. However, it remains unclear whether 3',5'-cAMP is universally present in the Firmicutes group of bacteria. We hypothesized that searching for proteins that bind 3',5'-cAMP might provide new insight into this question. Accordingly, we performed a genome-wide screen, and identified the essential Staphylococcus aureus tRNA m1G37 methyltransferase enzyme TrmD, which is conserved in all three domains of life, as a tight 3',5'-cAMP binding protein...
November 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27875551/crystal-structures-of-group-b-streptococcus-glyceraldehyde-3-phosphate-dehydrogenase-apo-form-binary-and-ternary-complexes
#9
Norbert Schormann, Chapelle A Ayres, Alexandra Fry, Todd J Green, Surajit Banerjee, Glen C Ulett, Debasish Chattopadhyay
Glyceraldehyde 3-phosphate dehydrogenase or GAPDH is an evolutionarily conserved glycolytic enzyme. It catalyzes the two step oxidative phosphorylation of D-glyceraldehyde 3-phosphate into 1,3-bisphosphoglycerate using inorganic phosphate and NAD+ as cofactor. GAPDH of Group B Streptococcus is a major virulence factor and a potential vaccine candidate. Moreover, since GAPDH activity is essential for bacterial growth it may serve as a possible drug target. Crystal structures of Group B Streptococcus GAPDH in the apo-form, two different binary complexes and the ternary complex are described here...
2016: PloS One
https://www.readbyqxmd.com/read/27873207/profiling-phosphopeptide-binding-domain-recognition-specificity-using-peptide-microarrays
#10
Michele Tinti, Simona Panni, Gianni Cesareni
Cellular organization and response to internal and external stimuli are mediated by an intricate web of protein interactions. Some of these interactions are regulated by covalent posttranslational modifications such as phosphorylation and acetylation. These modifications can change the chemical nature of the interaction interfaces and modulate the binding affinity of the interacting partners. In signal transduction, the most frequent modification is reversible phosphorylation of tyrosine, serine or threonine residues...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27872998/ppest-is-a-novel-pbat-degrading-polyesterase-identified-by-proteomic-screening-of-pseudomonas-pseudoalcaligenes
#11
Paal W Wallace, Karolina Haernvall, Doris Ribitsch, Sabine Zitzenbacher, Matthias Schittmayer, Georg Steinkellner, Karl Gruber, Georg M Guebitz, Ruth Birner-Gruenberger
A novel esterase, PpEst, that hydrolyses the co-aromatic-aliphatic polyester poly(1,4-butylene adipate-co-terephthalate) (PBAT) was identified by proteomic screening of the Pseudomonas pseudoalcaligenes secretome. PpEst was induced by the presence of PBAT in the growth media and had predicted arylesterase (EC 3.1.1.2) activity. PpEst showed polyesterase activity on both whole and milled PBAT film releasing terephthalic acid and 4-(4-hydroxybutoxycarbonyl)benzoic acid while end product inhibition by 4-(4-hydroxybutoxycarbonyl)benzoic acid was observed...
November 21, 2016: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/27864097/post-translational-regulation-by-structural-changes-of-4-dihydromethyltrisporate-dehydrogenase-a-key-enzyme-in-sexual-and-parasitic-communication-mediated-by-the-trisporic-acid-pheromone-system-of-the-fungal-fusion-parasite-parasitella-parasitica
#12
Sabrina Ellenberger, Anke Burmester, Stefan Schuster, Johannes Wöstemeyer
Sexual communication between complementary mating partners in the fungal group of zygomycetes is mediated by the trisporoid pheromone system. A key enzyme towards biosynthesis of hormonally active trisporoids is 4-dihydromethyltrisporate dehydrogenase (TSP1), an enzyme occurring in all zygomycetous fungi. Trisporic acid and some of its precursor molecules serve as pheromones for recognizing complementary mating partners and for induction of the differentiation program towards sexual spore formation. In the parasitic zygomycete Parasitella parasitica, a biotrophic fusion parasite infecting many other zygomycetes, these substances have an additional function: They are also responsible for host-parasite recognition and the formation of the characteristic infection structures...
November 15, 2016: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/27860279/targeting-myeloid-differentiation-protein-2-by-the-new-chalcone-l2h21-protects-lps-induced-acute-lung-injury
#13
Yali Zhang, Tingting Xu, Beibei Wu, Hongjin Chen, Zheer Pan, Yi Huang, Liqin Mei, Yuanrong Dai, Xing Liu, Xiaoou Shan, Guang Liang
Acute inflammatory diseases are the leading causes of mortality in intensive care units. Myeloid differentiation 2 (MD-2) is required for recognizing lipopolysaccharide (LPS) by toll-like receptor 4 (TLR4), and represents an attractive therapeutic target for LPS-induced inflammatory diseases. In this study, we report a chalcone derivative, L2H21, as a new MD2 inhibitor, which could inhibit LPS-induced inflammation both in vitro and in vivo. We identify that L2H21 as a direct inhibitor of MD-2 by binding to Arg(90) and Tyr(102) residues in MD-2 hydrophobic pocket using a series of biochemical experiments, including surface plasmon response, molecular docking and amino acid mutation...
November 18, 2016: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/27852804/toxin-resistant-isoforms-of-na-k-atpase-in-snakes-do-not-closely-track-dietary-specialization-on-toads
#14
Shabnam Mohammadi, Zachariah Gompert, Jonathan Gonzalez, Hirohiko Takeuchi, Akira Mori, Alan H Savitzky
Toads are chemically defended by bufadienolides, a class of cardiotonic steroids that exert toxic effects by binding to and disabling the Na(+)/K(+)-ATPases of cell membranes. Some predators, including a number of snakes, have evolved resistance to the toxic effects of bufadienolides and prey regularly on toads. Resistance in snakes to the acute effects of these toxins is conferred by at least two amino acid substitutions in the cardiotonic steroid binding pocket of the Na(+)/K(+)-ATPase. We surveyed 100 species of snakes from a broad phylogenetic range for the presence or absence of resistance-conferring mutations...
November 16, 2016: Proceedings. Biological Sciences
https://www.readbyqxmd.com/read/27842892/discovery-of-4-5-arylidene-4-oxothiazolidin-3-yl-methyl-benzoic-acid-derivatives-active-as-novel-potent-allosteric-inhibitors-of-protein-tyrosine-phosphatase-1b-in-silico-studies-and-in%C3%A2-vitro-evaluation-as-insulinomimetic-and-anti-inflammatory-agents
#15
Rosaria Ottanà, Paolo Paoli, Alexandra Naß, Giulia Lori, Venera Cardile, Ilenia Adornato, Archimede Rotondo, Adriana Carol Eleonora Graziano, Gerhard Wolber, Rosanna Maccari
New 4-{[5-arylidene-2-(4-fluorophenylimino)-4-oxothiazolidin-3-yl]methyl}benzoic acids (5) and 2-thioxo-4-thiazolidinone analogues (6) were synthesised as a part of a continuing search for new inhibitors of protein tyrosine phosphatase 1B (PTP1B), an enzyme which is implicated in metabolic disorders and inflammatory signaling. Most of the tested compounds were shown to be potent PTP1B inhibitors. Moreover, their inhibition mechanism was markedly influenced by the substituents in the positions 2 and 5, as kinetic studies indicated...
November 1, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27837168/microbial-derived-1-4-dihydroxy-2-naphthoic-acid-and-related-compounds-as-aryl-hydrocarbon-receptor-agonists-antagonists-structure-activity-relationships-and-receptor-modeling
#16
Yating Cheng, Un-Ho Jin, Laurie A Davidson, Robert S Chapkin, Arul Jayaraman, Phanourios Tamamis, Asuka Orr, Clint Allred, Michael S Denison, Anatoly Soshilov, Evelyn Weaver, Stephen Safe
1,4-Dihydroxy-2-naphthoic acid (1,4-DHNA) is a bacterial-derived metabolite that binds the aryl hydrocarbon receptor (AhR) and exhibits anti-inflammatory activity in the gut. The structure-dependent AhR activity of hydroxyl/carboxy-substituted naphthoic acids was determined in young adult mouse colonic (YAMC) cells and human Caco2 colon cancer cells using CYP1A1/CYP1B1 mRNAs as Ah-responsive genes. Compounds used in this study include 1,4-, 3,5- and 3,7-DHNA, 1,4-dimethoxy-2-naphthoic acid (1,4-DMNA), 1- and 4-hydroxy-2-naphthoic acid (1-HNA, 4-HNA), 1- and 2-naphthoic acid (1-NA, 2-NA), and 1- and 2-naphthol (1-NOH, 2-NOH)...
November 11, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27832206/structural-functional-and-phylogenetic-analysis-of-sperm-lysozyme-like-proteins
#17
Shalini Kalra, Mangottil Ayyappan Pradeep, Ashok K Mohanty, Jai K Kaushik
Sperm lysozyme-like proteins belonging to c-type lysozyme family evolved in multiple forms. Lysozyme-like proteins, viz., LYZL2, LYZL3 or SLLP1, LYZL4, LYZL5 and LYZL6 are expressed in the testis of mammals. Not all members of LYZL family have been uniformly and unambiguously identified in the genome and proteome of mammals. Some studies suggested a role of SLLP1 and LYZL4 in fertilization; however, the function of other LYZL proteins is unknown. We identified all known forms of LYZL proteins in buffalo sperm by LC-MS/MS...
2016: PloS One
https://www.readbyqxmd.com/read/27827794/molecular-insights-into-protein-synthesis-with-proline-residues
#18
Sergey Melnikov, Justine Mailliot, Lukas Rigger, Sandro Neuner, Byung-Sik Shin, Gulnara Yusupova, Thomas E Dever, Ronald Micura, Marat Yusupov
Proline is an amino acid with a unique cyclic structure that facilitates the folding of many proteins, but also impedes the rate of peptide bond formation by the ribosome. As a ribosome substrate, proline reacts markedly slower when compared with other amino acids both as a donor and as an acceptor of the nascent peptide. Furthermore, synthesis of peptides with consecutive proline residues triggers ribosome stalling. Here, we report crystal structures of the eukaryotic ribosome bound to analogs of mono- and diprolyl-tRNAs...
December 2016: EMBO Reports
https://www.readbyqxmd.com/read/27827323/sequence-variation-at-klk-and-wfdc-clusters-and-its-association-to-semen-hyperviscosity-and-other-male-infertility-phenotypes
#19
Patrícia Isabel Marques, Filipa Fonseca, Ana Sofia Carvalho, Diana A Puente, Isabel Damião, Vasco Almeida, Nuno Barros, Alberto Barros, Filipa Carvalho, Mikel Azkargorta, Felix Elortza, Hugo Osório, Rune Matthiesen, Victor Quesada, Susana Seixas
STUDY QUESTION: Are kallikreins (KLKs), the whey-acidic-protein four-disulfide core domain (WFDCs) and their neighbors, semenogelins (SEMGs), known to play a role in the cascade of semen coagulation and liquefaction, associated with male infertility? SUMMARY ANSWER: Several KLK and SEMG variants are overrepresented among hyperviscosity, asthenozoospermia and oligozoospermia, supporting an effect of abnormal semen liquefaction on the loss of semen quality and in lowering male reproductive fitness...
November 7, 2016: Human Reproduction
https://www.readbyqxmd.com/read/27825926/the-interaction-mode-of-the-acidic-region-of-the-cell-cycle-transcription-factor-dp1-with-tfiih
#20
Masahiko Okuda, Keigo Araki, Kiyoshi Ohtani, Yoshifumi Nishimura
The heterodimeric transcription factor E2F1-DP1 plays crucial roles in coordinating gene expression during G1/S cell cycle progression. For transcriptional activation, the transactivation domain (TAD) of E2F1 is known to interact with the TATA-binding protein of TFIID and the p62 subunit of TFIIH. It is generally believed that DP1 facilitates E2F1 binding to target DNA and does not possess a TAD. Here, we show that an acidic region of DP1, whose function has remained elusive, binds to the plekstrin homology (PH) domain of p62 with higher affinity than that of E2F1 and contributes to transcriptional activation...
November 4, 2016: Journal of Molecular Biology
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