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acid pocket

Rand Shahin, Iman Mansi, Lubna Swellmeen, Tahani Alwidyan, Nabil Al-Hashimi, Yaser Al-Qarar'h, Omar Shaheen
Targeting tropomycin kinase A (TrkA) by small molecule inhibitors is considered as a promising strategy for treating several human cancers. To achieve this goal, a ligand based QSAR model was applied using the Discovery studio 4.5 (DS 4.5). Hence, a total list of 161 TrkA inhibitors was investigated. The TrkA inhibitors were extensively explored to detect their optimal physicochemical properties and pharmacophoric binding modes, which were converted into numeric descriptors and allowed to compete within the context of the Genetic Function Algorithm (GFA) approximations to find the subset of terms that correlates best with the activity...
January 13, 2018: Journal of Molecular Graphics & Modelling
Ge Zhao, Jianrong Wang, Qingyun Tang, Dongming Lan, Yonghua Wang
MAS1 is a lipase isolated from Streptomyces sp. strain W007 with potential application in biotechnology. Structural analysis of MAS1 lipase showed that eight amino acids with bulkier side located in the substrate-binding pocket may be involved in affecting catalytic performance. Alanine substitutions of those residues were conducted to reduce steric clash of catalyzed pocket and probe their functional roles. The k cat /K m of mutants H108A, F153A, and V233A increased to 2.3-, 2.1-, and 1.4-fold, respectively...
February 15, 2018: Molecular Biotechnology
Yongkun Chen, Tian Bai, Wenfei Zhu, Rongbao Gao, Zhihong Deng, Yi Shi, Shumei Zou, Yiwei Huang, Xiyan Li, Fangcai Li, Zhaomin Feng, Tao Chen, Jing Yang, Dayan Wang, Lidong Gao, Yuelong Shu
Human influenza viruses preferentially bind to sialic acid-α2,6-galactose (SAα2,6Gal) receptors, which are predominant in human upper respiratory epithelia, whereas avian influenza viruses preferentially bind to SAα2,3Gal receptors. However, variants with amino acid substitutions around the receptor-binding sites of the hemagglutinin (HA) protein can be selected after several passages of human influenza viruses from patients' respiratory samples in the allantoic cavities of embryonated chicken eggs. In this study, we detected an egg-adapted HA S190R mutation in the pandemic H1N1 virus 2009 (pdmH1N1), and evaluated the effects of this mutation on receptor binding affinity and pathogenicity in mice...
February 10, 2018: Science China. Life Sciences
Anne Dittrich, David Scheibner, Ahmed H Salaheldin, Jutta Veits, Marcel Gischke, Thomas C Mettenleiter, Elsayed M Abdelwhab
Wild birds are the reservoir for low-pathogenic avian influenza viruses, which are frequently transmitted to domestic birds and occasionally to mammals. In 2014, an H10N7 virus caused severe mortality in harbor seals in northeastern Europe. Although the hemagglutinin (HA) of this virus was closely related to H10 of avian H10N4 virus, it possessed unique nonsynonymous mutations, particularly in the HA1 subunit in or adjacent to the receptor binding domain and proteolytic cleavage site. Here, the impact of these mutations on virus replication was studied in vitro...
February 14, 2018: Viruses
Hesham Haffez, David R Chisholm, Natalie J Tatum, Roy Valentine, Christopher Redfern, Ehmke Pohl, Andrew Whiting, Stefan Przyborski
Retinoids, such as all-trans-retinoic acid (ATRA), regulate cellular differentiation and signalling pathways in chordates by binding to nuclear retinoic acid receptors (RARα/β/γ). Polar interactions between receptor and ligand are important for binding and facilitating the non-polar interactions and conformational changes necessary for RAR-mediated transcriptional regulation. The constraints on activity and RAR-type specificity with respect to the structural link between the polar and non-polar functions of synthetic retinoids are poorly understood...
February 10, 2018: Bioorganic & Medicinal Chemistry
Jungki Min, Lalith Perera, Juno M Krahn, Christine M Jewell, Andrea F Moon, John A Cidlowski, Lars C Pedersen
Glucocorticoid receptor β (GRβ) is associated with glucocorticoid resistance via dominant negative regulation of GRα. To better understand how GRβ functions as a dominant negative inhibitor of GRα at a molecular level, we determined the crystal structure of the ligand binding domain of GRβ complexed with antagonist RU-486. The structure reveals that RU-486 binds in the same ligand binding pocket as in GRα and the unique C-terminal amino acids of GRβ are mostly disordered. Binding energy analysis suggests that these C-terminal residues of GRβ do not contribute to RU-486 binding...
February 5, 2018: Molecular and Cellular Biology
Zheng Li, Xue Xu, Jie Hou, Shaohong Wang, Hongwei Jiang, Luyong Zhang
The free fatty acid receptor 1 (FFA1) plays an important role in amplifying insulin secretion in a glucose dependent manner. We have previously reported a series of FFA1 agonists with thiazole scaffold exemplified by compound 1, and identified a small hydrophobic subpocket partially occupied by the methyl group of compound 1. Herein, we describe further structure optimization to better fit the small hydrophobic subpocket by replacing the small methyl group with other hydrophobic substituents. All of these efforts resulted in the identification of compound 6, a potent FFA1 agonist (EC 50 = 39...
February 1, 2018: Bioorganic Chemistry
Edjane R Dos Santos, Angelica E Graminha, Mario S Schultz, Isabel Correia, Heloisa S Selistre-de-Araújo, Rodrigo S Corrêa, Javier Ellena, Elisângela de Paula S Lacerda, João Costa Pessoa, Alzir A Batista
Thirteen new ruthenium amino acid complexes were synthesized and characterized. They were obtained by the reaction of α-amino acids (AA) with [RuCl2(P-P)(N-N)], where P-P=1,4-bis(diphenylphosphino)butane (dppb) or 1,3-bis(diphenylphosphino)propane (dppp) and N-N=4,4'-dimethyl-2,2'-bipyridine (4'-Mebipy), 5,5'-dimethyl-2,2'-bipyridine (5'-Mebipy) or 4,4'-Methoxy-2-2'-bipyridine (4'-MeObipy). This afforded a family of complexes formulated as [Ru(AA-H)(P-P)(N-N)]PF6, where AA=glycine (Gly), L-alanine (Ala), L-valine (Val), L-tyrosine (Tyr), L-tryptophan (Trp), L-histidine (His) and L-methionine (Met)...
December 23, 2017: Journal of Inorganic Biochemistry
Jyoti Bala, Srinivasan Chinnapaiyan, Rajib Kumar Dutta, Hoshang Unwalla
Aptamers are high affinity single-stranded nucleic acid or protein ligands which exhibit specificity and avidity comparable to, or exceeding that of antibodies and can be generated against most targets. The functionality of aptamers is based on their unique tertiary structure, complexity and their ability to attain unique binding pockets by folding. Aptamers are selected in vitro by a process called Systematic Evolution of Ligands by Exponential enrichment (SELEX). The Kd values for the selected aptamer are often in the picomolar to low nanomolar range...
February 12, 2018: RNA Biology
Wei-Fei Chen, Stephane Rety, Hai-Lei Guo, Yang-Xue Dai, Wen-Qiang Wu, Na-Nv Liu, Daniel Auguin, Qian-Wen Liu, Xi-Miao Hou, Shuo-Xing Dou, Xu-Guang Xi
Helicase DHX36 plays essential roles in cell development and differentiation at least partially by resolving G-quadruplex (G4) structures. Here we report crystal structures of the Drosophila homolog of DHX36 (DmDHX36) in complex with RNA and a series of DNAs. By combining structural, small-angle X-ray scattering, molecular dynamics simulation, and single-molecule fluorescence studies, we revealed that positively charged amino acids in RecA2 and OB-like domains constitute an elaborate structural pocket at the nucleic acid entrance, in which negatively charged G4 DNA is tightly bound and partially destabilized...
January 29, 2018: Structure
Sangwoo Kim, Kyung-Jin Kim
Acyl-CoA oxidases (ACOXs) play important roles in lipid metabolism, including peroxisomal fatty acid β-oxidation by the conversion of acyl-CoAs to 2-trans-enoyl-CoAs. The yeast Yarrowia lipolyticacan utilize fatty acidsas a carbon source and thus has extensive biotechnological applications. The crystal structure of ACOX3from Y. lipolytica(YlACOX3) was determinedat a resolution of2.5 Å. It contained two molecules per asymmetric unit, and the monomeric structure was folded into four domains, Nα, Nβ, Cα1 and Cα2domains...
February 13, 2018: Journal of Microbiology and Biotechnology
Asuka A Orr, Arul Jayaraman, Phanourios Tamamis
Docking algorithms have been widely used to elucidate ligand:receptor interactions that are important in biological function. Here, we introduce an in-house developed docking-refinement protocol that combines the following innovative features. (1) The use of multiple short molecular dynamics (MD) docking simulations, with residues within the binding pocket of the receptor unconstrained, so that the binding modes of the ligand in the binding pocket may be exhaustively examined. (2) The initial positioning of the ligand within the binding pocket based on complementary shape, and the use of both harmonic and quartic spherical potentials to constrain the ligand in the binding pocket during multiple short docking simulations...
2018: Methods in Molecular Biology
Quan Chi, Zhixiong Li, Juan Huang, Jieyao Ma, Xian Wang
The binding information of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) with bovine and human serum albumins was investigated and characterized in details by using a combination method of electrospray ionization mass spectrometry (ESI-MS), fluorescence, circular dichroism (CD) and molecular docking (MD). The ESI-MS analysis revealed that maximally eight PFOA or PFOS molecules could bind to serum albumins at high mole ratios of PFOA/PFOS. Association constants were measured by ESI-MS and suggested that PFOS had a better binding affinity than PFOA...
February 3, 2018: Chemosphere
Yuanmei Zhu, Xiujuan Zhang, Xiaohui Ding, Huihui Chong, Sheng Cui, Jinsheng He, Xinquan Wang, Yuxian He
Enfuvirtide (T20) is the only viral fusion inhibitor approved for clinical use, but it has relatively weak anti-HIV activity and easily induces drug resistance. In succession to T20, T1249 has been designed as a 39-mer peptide composed of amino acid sequences derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV); however, its development has been suspended due to formulation difficulties. We recently developed a T20-based lipopeptide (LP-40) showing greatly improved pharmaceutical properties. Here, we generated a T1249-based lipopeptide, termed LP-46, by replacing its C-terminal tryptophan-rich sequence with fatty acid...
February 7, 2018: Journal of Biological Chemistry
Julian Zaugg, Yosephine Gumulya, Mikael Boden, Alan Edward Mark, Alpeshkumar K Malde
Molecular dynamics simulations and free energy calculations have been used to investigate the effect of ligand binding on the enantioselectivity of an epoxide hydrolase (EH) from Aspergillus niger. Despite sharing a common mechanism, a wide range of alternative mechanisms have been proposed to explain the origin of enantiomeric selectivity in EHs. By comparing the interactions of (R)- and (S)-glycidyl phenyl ether (GPE) with both the wild type (WT, E = 3) and a mutant showing enhanced enantioselectivity to GPE (LW202, E = 193) we have examined whether enantioselectivity is due to differences in the binding pose, the affinity for the (R)- or (S)- enantiomers or a kinetic effect...
February 9, 2018: Journal of Chemical Information and Modeling
Shaghayegh Dezvarei, Joel H Z Lee, Stephen G Bell
The stereoselective oxidation of hydrocarbons is an area of research where enzyme biocatalysis can make a substantial impact. The cyclic ketone isophorone was stereoselectively hydroxylated (≥95%) by wild-type CYP102A1 to form (R)-4-hydroxyisophorone, an important chiral synthon and flavour and fragrance compound. CYP102A1 variants were also selective for 4-hydroxyisophorone formation and the product formation rate increased over the wild-type enzyme by up to 285-fold, with the best mutants being R47L/Y51F/I401P and A74G/F87V/L188Q...
April 2018: Enzyme and Microbial Technology
Chao Wang, Shuang Chen, Hong-Bin Zhang, Yao Li, Xue-Qin Hu
Dextran produced by dextransucrase hold strong potential for industrial applications. The exact determinants of the linkage specificity of glucansucrase enzymes have remained largely unknown. Previous studies have investigated the relationships between structure and linkage specificity of the dextransucrase DSR from Leuconostoc mesenteroides by the site-directed mutagenesis of the catalytic pocket. The glycosidic linkage of dextran produced by mutant enzymes changed slightly by 3% to 20%. The mutagenesis dextransucrases were constructed by inserting an amino acid into a catalytic pocket to investigate the product specificities of dextransucrase thoroughly...
February 2, 2018: International Journal of Biological Macromolecules
Jing Zhao, Mengjun Xue, Dorota Gudanis, Hanna Gracz, Gerhard H Findenegg, Zofia Gdaniec, Stefan Franzen
Dehaloperoxidase-hemoglobin is the first hemoglobin identified with biologically-relevant oxidative functions, which include peroxidase, peroxygenase and oxidase activities. Herein we report a study of the protein backbone dynamics of DHP using heteronuclear NMR relaxation methods and molecular dynamics (MD) simulations to address the role of protein dynamics in switching from one function to another. The results show that DHP's backbone helical regions and turns have average order parameters of S2 = 0...
January 12, 2018: Journal of Inorganic Biochemistry
Qiuchen Zheng, Noel D Lazo
The self-assembly of insulin to form amyloid fibrils has been widely studied because it is a significant problem in the medical management of diabetes and is an important model system for the investigation of amyloid formation and its inhibition. A few inhibitors of insulin fibrillation have been identified with potencies that could be higher. Knowledge of how these work at the molecular level is not known but important for the development of more potent inhibitors. Here we show that rosmarinic acid completely inhibits amyloid formation by dimeric insulin at pH 2 and 60 °C...
February 5, 2018: Journal of Physical Chemistry. B
Mamatha S Shetty, Amitha Ramesh, Prasanna Kumar Shetty, Priyanka Agumbe
Background and Objectives: Preeclampsia is a challenging disease of human pregnancy that affects the mother and her foetus. It is a common obstetric syndrome of undefined aetiology affecting 7-10% of pregnant women. This study aimed to investigate the total antioxidant capacity (TAC), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, malondialdehyde levels, uric acid, vitamin C, and vitamin E levels in serum and saliva of preeclamptic and normotensive pregnant women with and without periodontitis...
February 2018: Journal of Obstetrics and Gynaecology of India
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