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acid pocket

Chaurasia Priya Dayashankar, P C Deepika, Basavarajaiah Siddaramaiah
BACKGROUND: Conventional periodontal therapy with various bone grafts has limited scope and the results are not predictable. To improve their utility, the hybridization of bioceramics and biodegradable polymers has been widely adopted to reform the mechanical properties of bone grafts. One such biodegradable polymer is POC (Poly 1,8 octanediol). Secondly, citric acid is considered as the key material in bone mineralization, which is related to the overall stability, strength and fracture resistance of bone...
July 2017: Contemporary Clinical Dentistry
Amir Inbal, Benjamin T Lemelman, Eran Millet, Andrew Greensmith
Background: Auricular reconstruction is one of the most challenging procedures in plastic surgery. An adequate skin envelope is essential for cartilage framework coverage, yet few good options exist without additional surgery. We propose a novel method for minimally invasive tissue expansion, using hyaluronic acid (HA) filler to allow for single-stage ear reconstruction. Objectives: To introduce the novel concept of HA filler for tissue expansion in ear reconstruction, and as an alternative to traditional expansion techniques...
July 20, 2017: Aesthetic Surgery Journal
Anurag Singh Chauhan, Md Yousuf Ansari, Rani Mansuri, Manas Ranjan Dikhit, Vahab Ali, Ganesh Chandra Sahoo, Pradeep Das
Acid-sensing ion channels (ASICs) are ligand/proton-gated ion channels belonging to the family of the degenerin/epithelial Na(+) channel (DEG/ENaC). They function as a sodium-selective pore for Ca(2+) entry into neuronal cells during pathological conditions. The blocking of this channel has therapeutic importance, because at basal physiological pH (7.2), it is in a closed state and under a more acidic condition, and the ASIC1a ion channel is activated. To investigate the different states of the hASIC1a channel based on mutational analysis, structure based virtual screening and molecular dynamics simulation studies...
October 17, 2017: Journal of Biomolecular Structure & Dynamics
Dennis-Helmut Manz, Peng-Cheng Duan, Sebastian Dechert, Serhiy Demeshko, Rainer Oswald, Michael John, Ricardo A Mata, Franc Meyer
A compartmental ligand scaffold HL with two β-diketiminato binding sites spanned by a pyrazolate bridge gave a series of dinuclear nickel(II) dihydride complexes M[LNi2(H)2], M = Na (Na∙2), K (K∙2), which were isolated after reacting the precur-sor complex [LNi2(µ-Br)] (1) with MHBEt3 (M = Na and K). Crystallographic characterization showed the two hydride lig-ands to be directed into the bimetallic pocket, closely interacting with the alkali metal cation. Treatment of K∙2 with diben-zo(18-crown-6) led to the separated ion pair [LNi2(H)2][K(DB18C6)] (2[K(DB18C6)])...
October 16, 2017: Journal of the American Chemical Society
Shaymaa E Kassab, Mohammed A Khedr, Hamed I Ali, Mohamed M Abdalla
New ring-extended analogs of indomethacin were designed based on the structure of active binding site of both COX-1 and COX-2 isoenzymes and the interaction pattern required for selective inhibition of COX-2 to improve its selectivity against COX-2. The strategy adopted for designing the new inhibitors involved i) ring extension of indomethacin to reduce the possibility of analogs to be accommodated into the narrow hydrophobic tunnel of COX-1, ii) deletion of carboxylic acid to reduce the possibility of inhibitor to form salt bridge with Arg120 and eventually prevent COX-1 inhibition, and iii) introduction of methylsulfonyl group to increase the opportunity of the analogs to interact with the polar side pocket that's is crucial for inhibition process of COX-2...
September 28, 2017: European Journal of Medicinal Chemistry
Sabine Meyer, Andi Mainz, Jan-Christoph Kehr, Roderich D Süssmuth, Elke Dittmann
Biosynthesis of the potent cyanobacterial hepatotoxin microcystin involves isopeptide bond formation via the carboxylic acid side chains of D-glutamate and β-methyl- D-aspartate. Analysis of the in vitro activation profiles of the two corresponding adenylation domains McyE-A and McyB-A2 either in a didomain or a tridomain context with the cognate thiolation and the upstream condensation domain revealed that substrate activation of both domains strictly depends on the presence of the condensation domains. We further identified two key amino acids in the binding pockets of both adenylation domains that could serve as a bioinformatic signature of isopeptide bond forming modules incorporating D-glutamate or D-aspartate...
October 11, 2017: Chembiochem: a European Journal of Chemical Biology
Sascha Georg Keller, Andrea Pannwitz, Hendrik Mallin, Oliver Wenger, Thomas R Ward
Long-lived photo-driven charge separation is demonstrated by assembling a triad on a protein scaffold. For this purpose, a biotinylated triarylamine was added to a Ru(II)- streptavidin conjugate bearing a methyl viologen electron acceptor covalently linked to the N-terminus of streptavidin. To improve the rate and lifetime of the electron transfer a negative patch consisting of up to three negatively charged amino acids was engineered via mutagenesis close to the biotin-binding pocket of streptavidin. Time-resolved laser spectroscopy revealed that the covalent attachment and the negative patch was beneficial for charge separation within the streptavidin hosted triad: the charge separate state was generated within the duration of the excitation laser pulse, and lifetimes up to 3120 ns could be achieved with the optimized supramolecular triad...
October 10, 2017: Chemistry: a European Journal
Lingyun Qin, Huili Liu, Rong Chen, Jingjing Zhou, Xiyao Cheng, Yao Chen, Yongqi Huang, Zhengding Su
The oncoprotein MdmX (Mouse double minute X) is highly homologous to Mdm2 (Mouse double minute 2) regarding their amino acid sequences and three-dimensional conformations, but Mdm2 inhibitors exhibit very weak affinity for MdmX, providing an excellent model for exploring how protein conformation distinguishes and adapts inhibitor-binding. The intrinsic conformation flexibility of proteins plays pivotal roles in determining and predicting the binding properties and the design of inhibitors. Although the molecular dynamics simulation approach enables the understanding of protein-ligand interactions, the mechanism un-derlying how a flexible binding pocket adapts an inhibitor is less explored experimentally...
October 12, 2017: Biochemistry
Indu Kumari, Mushtaq Ahmed, Yusuf Akhter
Trichodiene synthase, a terpene fold enzyme catalyzes the first reaction of trichodermin biosynthesis that is an economically important secondary metabolite. Sequence search analysis revealed that the proteins containing terpene fold are present in bacteria, fungi and plants. Terpene fold protein from Selaginella moellendorffii, a lycophyte, appeared at the interface of the microbes and plants in the evolutionary scale. Amino acid residues present around the catalytic pocket determines the size of the substrate as well as product molecules...
October 7, 2017: Biochimie
Melinda Hauser, Chen Qian, Steven T King, Sarah Kauffman, Fred Naider, Robert L Hettich, Jeffrey M Becker
We are developing a rapid, time-resolved method using laser-activated cross-linking to capture protein-peptide interactions as a means to interrogate the interaction of serum proteins as delivery systems for peptides and other molecules. A model system was established to investigate the interactions between bovine serum albumin (BSA) and 2 peptides, the tridecapeptide budding-yeast mating pheromone (α-factor) and the decapeptide human gonadotropin-releasing hormone (GnRH). Cross-linking of α-factor, using a biotinylated, photoactivatable p-benzoyl-L-phenylalanine (Bpa)-modified analog, was energy-dependent and achieved within seconds of laser irradiation...
October 10, 2017: Journal of Molecular Recognition: JMR
Yipeng Ma, Rana Abdelnabi, Leen Delang, Mathy Froeyen, Walter Luyten, Johan Neyts, Carmen Mirabelli
4-dimethylamino benzoic acid (compound 12, synonym: 4EDMAB) was identified as an in vitro inhibitor of Coxsackie virus B3 (CVB3) replication in CPE-based assays (EC50 of 9.1 ± 1.5 μM). Next, the activity of twenty-three analogues was assessed, their structure-activity relationship was deduced and a more potent analogue was identified (EC50 of 2.6 ± 0.5 μM). The antiviral activity of 4EDMAB was further confirmed by quantifying viral RNA yield. Time-of-drug-addition assay revealed that 4EDMAB exerts its antiviral activity at the early stages of virus replication...
October 7, 2017: Antiviral Research
Lars Jørgensen, Anas Al-Khawaja, Stefanie Kickinger, Stine Byskov Vogensen, Jonas Skovgaard-Petersen, Emil Rosenthal Jensen, Nrupa Borkar, Rebekka Löffler, Karsten K Madsen, Hans Bräuner-Osborne, Arne Schousboe, Gerhard F Ecker, Petrine Wellendorph, Rasmus Prætorius Clausen
N-(1-Benzyl-4-piperidinyl)-2,4-dichlorobenzamide 5 (BPDBA) is a non-competitive inhibitor of the betaine/GABA transporter 1 (BGT1). We here report the synthesis and structure-activity relationship of 71 analogues. We identify 26m as a more soluble 2,4-Cl substituted 3-pyridine analogue with retained BGT1 activity and an improved off-target profile compared to 5. We performed radioligand-based uptake studies at chimeric constructs between BGT1 and GAT3, experiments with site-directed mutated transporters and computational docking in a BGT1 homology model based on the newly determined X-ray crystal structure of the human serotonin transporter (hSERT)...
October 9, 2017: Journal of Medicinal Chemistry
Yanbin Feng, Yayue Wang, Jiao Liu, Yinghui Liu, Xupeng Cao, Song Xue
Acyl-ACP thioesterase (TE) catalyzes the hydrolysis of thioester bonds during type II fatty acid synthesis and directly determines fatty acid chain length. Most TEs are responsible for recognition of 16:0 and 18:1 substrates, while specific TEs interrupt acyl-ACP elongation at C8-C14. However, the acyl selection mechanism of TE has not been thoroughly elucidated to date. In this study, the crystal structure of the C12-specific thioesterase FatB from Umbellularia californica, which consists of two independent hotdog domains, was determined...
October 9, 2017: ACS Chemical Biology
Reinke T Müller, Timothy Travers, Hi-Jea Cha, Joshua L Phillips, S Gnanakaran, Klaas M Pos
The functionally important switch-loop of the trimeric multidrug transporter AcrB separates the access and deep drug binding pockets in every protomer. This loop, comprising 11 amino acid residues, has been shown to be crucial for substrate transport, as drugs have to travel past the loop to reach the deep binding pocket and from there are transported outside the cell via the connected AcrA and TolC channels. It contains four symmetrically arranged glycine residues suggesting that flexibility is a key feature for pump activity...
October 5, 2017: Journal of Molecular Biology
Baiyun Wang, Xue Chen, Zixi Wang, Wei Xiong, Tao Xu, Xinyuan Zhao, Yang Cao, Yanru Guo, Lin Li, She Chen, Song Huang, Xiaodong Wang, Min Fang, Zhirong Shen
Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding acids, reactions that are coupled to the reduction of NAD(+) to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and dihydrolipoic acid (DHLA) as electron donors to reduce NAD(+) to NADH. The GSH/DHLA-dependent NAD(+)-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket...
September 15, 2017: Oncotarget
Serena Monaco, Louise Elizabeth Tailford, Nathalie Juge, Jesus Angulo
STD NMR spectroscopy is extensively used to obtain epitope maps of ligands binding to protein receptors, revealing structural details of the interaction, which is key to direct lead optimization efforts in drug discovery. However, it does not give information about the nature of the amino acids surrounding the ligand in the binding pocket. Here we report the development of a novel protocol, Differential Epitope Mapping by STD NMR (DEEP-STD NMR), to identify the type of protein residues contacting the ligand...
October 4, 2017: Angewandte Chemie
Yogesh B Khandokar, Parul Srivastava, Nathan Cowieson, Subir Sarker, David Aragao, Shubagata Das, Kate M Smith, Shane R Raidal, Jade K Forwood
Thioesterases catalyze the cleavage of thioester bonds within many activated fatty acids and acyl-CoA substrates. They are expressed ubiquitously in both prokaryotes and eukaryotes and are subdivided into 25 thioesterase families according to their catalytic active site, protein oligomerization, and substrate specificity. While many of these enzyme families are well characterized in terms of function and substrate specificity, regulation across most thioesterase families is poorly understood. Here, we characterized a TE6 thioesterase from the bacterium Neisseria meningitidis...
October 2, 2017: Journal of Biological Chemistry
Kathy Hiu Laam Po, Edward Wai Chi Chan, Sheng Chen
This work investigated the molecular events driving the evolution of the CTX-M-type β-lactamases by DNA shuffling of fragments of the blaCTX-M-14 and blaCTX-M-15 genes. Analysis of a total of 51 hybrid enzymes showed that enzymatic activity could be maintained in most cases, yet active hybrids possessed fewer amino acid substitutions than those that were inactive, suggesting that point mutations in the constructs, rather than re-shuffling fragments of the two target genes, would more likely cause disruption of CTX-M activity...
October 2, 2017: Antimicrobial Agents and Chemotherapy
Aleksandra Miszkiel, Marek Wojciechowski
Glucosamine-6-phosphate synthase (EC is responsible for catalysis of the first and practically irreversible step in hexosamine metabolism. The final product of this pathway, uridine 5' diphospho N-acetyl-d-glucosamine (UDP-GlcNAc), is an essential substrate for assembly of bacterial and fungal cell walls. Moreover, the enzyme is involved in phenomenon of hexosamine induced insulin resistance in type II diabetes, which makes of it a potential target for anti-fungal, anti-bacterial and anti-diabetic therapy...
September 18, 2017: Journal of Molecular Graphics & Modelling
Patrick N Blank, Golda H Barrow, Wayne K W Chou, Lian Duan, David E Cane, David W Christianson
The sesquiterpene cyclase epi-isozizaene synthase (EIZS) catalyzes the cyclization of farnesyl diphosphate to form the tricyclic hydrocarbon precursor of the antibiotic albaflavenone. The hydrophobic active site pocket of EIZS serves as a template as it binds and chaperones the flexible substrate and carbocation intermediates through the conformations required for a multistep reaction sequence. We previously demonstrated that the substitution of hydrophobic residues with other hydrophobic residues remolds the template and expands product chemodiversity [Li, R...
October 17, 2017: Biochemistry
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