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Unnatural amino acid

Antonio M Lopes, Patricia Domingues, Roland Zell, Benjamin G Hale
Rational characterization of virulence and host-adaptive markers in the multifunctional influenza A virus NS1 protein is hindered by a lack of comprehensive knowledge about NS1-host protein-protein interfaces. Here, we surveyed the impact of amino-acid variation in NS1 at its structurally-defined binding site for host p85β, a regulator of phosphoinositide-3 kinase (PI3K) signaling. Structure-guided alanine-scanning of all viral residues at this interface defined 10 positions contributing to the interaction, with residues 89, 95, 98, 133, 145 and 162 being most important...
August 16, 2017: Journal of Virology
Jin-Ling Dai, Nan-Qi Shao, Jin Zhang, Run-Ping Jia, Dong-Hui Wang
A Cu(II)-catalyzed ortho-selective functionalization of free phenols with trifluoroborates to afford Csp2-Csp3 coupling products under mild conditions has been developed. A variety of functional groups on the phenol and the potassium ami-nomethyltrifluoroborate substrates were found compatible, fur-nishing the corresponding products in moderate to excellent yields. A single-electron transfer radical coupling mechanism involving a six-membered transition state is proposed to rationalize the high levels of ortho-selectivity in the reaction...
August 14, 2017: Journal of the American Chemical Society
Lu Yang, Elliott M Dolan, Sophia K Tan, Tianyun Lin, Eduardo D Sontag, Sagar Khare
The construction of stimulus-responsive supramolecular complexes of metabolic pathway enzymes, inspired by natural multi-enzyme assemblies (metabolons), provides an attractive avenue for efficient and spatio-temporally controllable one-pot biotransformations. We constructed a phosphorylation- and optically-responsive metabolon for the biodegradation of the environmental pollutant 1,2,3-trichloropropane (TCP). The three enzymes in of a synthetic degradation pathway were fused to engineered variants of the peptide-binding domains (SH2, SH3; the latter redesigned to incorporate an unnatural photocrosslinkable amino acid) or their corresponding binding peptides, and enzyme co-localization in response to phosphorylation and UV-light was demonstrated...
August 10, 2017: Chembiochem: a European Journal of Chemical Biology
Xi Chen, Yunfeng Cui, Xinkuan Cheng, Jinhui Feng, Qiaqing Wu, Dunming Zhu
d-2-Aminobutyric acid is an unnatural amino acid serving as an important intermediate in pharmaceutical production. Developing a synthetic method that uses cheaper starting materials and produces less by-product is a pressing demand. A tri-enzymatic catalytic system, which is composed of l-threonine ammonia lyase (l-TAL), d-amino acid dehydrogenase (d-AADH), and formate dehydrogenase (FDH), has thus been developed for the synthesis of d-2-aminobutyric acid with high optical purity. In this cascade reaction, the readily available l-threonine serves as the starting material, carbon dioxide and water are the by-products...
August 2017: ChemistryOpen
Luciano Ricci, Lorenzo Sernissi, Dina Scarpi, Francesca Bianchini, Alessandro Contini, Ernesto G Occhiato
The conformational analysis of linear and cyclic peptides incorporating 2,3-methanopipecolic acids (or Cyclopropane Pipecolic Acids, CPAs) as conformationally constrained α-amino acids is reported. Compared to peptides containing proline or pipecolic acid, a striking increase of the cis isomer (42-92%) around the CPA amide bond is observed, both in water and organic solvents, when these unnatural amino acids are embodied in linear amino acid sequences. The rotational barrier around the same bond in water was calculated, giving results comparable to that for the prolyl cis/trans isomerization...
August 16, 2017: Organic & Biomolecular Chemistry
Raffaella Bucci, Priyadip Das, Filomena Iannuzzi, Marco Feligioni, Raffaella Gandolfi, Maria Luisa Gelmi, Meital Reches, Sara Pellegrino
The development of molecular carriers able to carry molecules directly into the cell is an area of intensive research. Cationic nanoparticles are effective delivery systems for several classes of molecules, such as anticancer agents, oligonucleotides and antibodies. Indeed, a cationic charge on the outer surface allows a rapid cellular uptake together with the possibility of carrying negatively charged molecules. In this work, we studied the self-assembly of an ultra-short ααβ-tripeptide containing an l-Arg-l-Ala sequence and an unnatural fluorine substituted β(2,3)-diaryl-amino acid...
August 16, 2017: Organic & Biomolecular Chemistry
Shereen Jabar, Luke Adams, Yao Wang, Luigi Aurelio, Bim Graham, Gottfried Otting
Intermolecular 1H-1H nuclear Overhauser effects (NOE) present a powerful tool to assess contacts between proteins and binding partners, but are difficult to identify for complexes of high molecular weight. We show that intermolecular NOEs can readily be observed following chemical labeling with t-butyl or trimethylsilyl groups. Proteins can be furnished with t-butyl or TMS groups site-specifically using genetically encoded unnatural amino acids or by chemical modification of single cysteine residues. No isotope labeling is required...
August 1, 2017: Chemistry: a European Journal
Kambiz M Hamadani, Jesse Howe, Madeleine K Jensen, Peng Wu, Jamie H D Cate, Susan Marqusee
Biomolecular systems exhibit many dynamic and biologically relevant properties, such as conformational fluctuations, multistep catalysis, transient interactions, folding, and allosteric structural transitions. These properties are challenging to detect and engineer using standard ensemble-based techniques. To address this drawback, single-molecule methods offer a way to access conformational distributions, transient states, and asynchronous dynamics inaccessible to these standard techniques. Fluorescence-based single molecule approaches are parallelizable and compatible with multiplexed detection; to date, however, they have remained limited to serial screens of small protein libraries...
July 28, 2017: Journal of Biological Chemistry
Jinfan Wang, Anthony C Forster
Aminoacyl-tRNAs containing a deoxy substitution in the penultimate nucleotide (C75 2'OH → 2'H) have been widely used in translation for incorporation of unnatural amino acids (AAs). However, this supposedly innocuous modification surprisingly increased peptidyl-tRNA(Ala)ugc drop off in biochemical assays of successive incorporations. Here we predict the function of this tRNA 2'OH in the ribosomal A, P and E sites using recent co-crystal structures of ribosomes and tRNA substrates and test these structure-function models by systematic kinetics analyses...
July 27, 2017: Scientific Reports
Xin Shang, Nanxi Wang, Ronald Cerny, Wei Niu, Jiantao Guo
We demonstrated a general protection-deprotection strategy for the design of fluorescent protein biosensors through the construction of a turn-on Hg(2+) sensor. A combination of fluorescent protein engineering and unnatural amino acid mutagenesis was used. Unlike previously reported fluorescent protein-based Hg(2+) sensors that relied on the binding of Hg(2+) to the sulfhydryl group of cysteine residues, a well-established chemical reaction, oxymercuration, was transformed into biological format and incorporated into our sensor design...
July 28, 2017: ACS Sensors
Maartje Westhoff, Christopher I Murray, Jodene Eldstrom, David Fedida
The slow delayed rectifier potassium current (IKs) is a key repolarizing current during the cardiac action potential. It consists of four KCNQ1 α-subunits and up to four KCNE1 β-subunits, which are thought to reside within external clefts of the channel. The interaction of KCNE1 with KCNQ1 dramatically delays opening of the channel but the mechanisms by which this occur are not yet fully understood. Here, we have used unnatural amino acid photo-cross-linking to investigate the dynamic interactions that occur between KCNQ1 and KCNE1 during activation gating...
July 25, 2017: Biophysical Journal
Maziar S Ardejani, Evan T Powers, Jeffery W Kelly
The rates and equilibria of the folding of biopolymers are determined by the conformational preferences of the subunits that make up the sequence of the biopolymer and by the interactions that are formed in the folded state in aqueous solution. Because of the centrality of these processes to life, quantifying conformational propensities and interaction strengths is vitally important to understanding biology. In this Account, we describe our use of peptide model systems that fold cooperatively yet are small enough to be chemically synthesized to measure such quantities...
August 15, 2017: Accounts of Chemical Research
Shuni Wang, Shengbin Zhou, Jiang Wang, Yong Nian, Aki Kawashima, Hiroki Moriwaki, José L Aceña, Vadim A Soloshonok, Hong Liu
No abstract text is available yet for this article.
July 18, 2017: Journal of Organic Chemistry
Jordan K Villa, Hong-Anh Tran, Megha Vipani, Stephanie Gianturco, Konark Bhasin, Brent L Russell, Elizabeth J Harbron, Douglas D Young
The ability to modulate protein function through minimal perturbations to amino acid structure represents an ideal mechanism to engineer optimized proteins. Due to the novel spectroscopic properties of green fluorescent protein, it has found widespread application as a reporter protein throughout the fields of biology and chemistry. Using site-specific amino acid mutagenesis, we have incorporated various fluorotyrosine residues directly into the fluorophore of the protein, altering the fluorescence and shifting the pKa of the phenolic proton associated with the fluorophore...
July 16, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Ewa Żesławska, Anna Jakubowska, Wojciech Nitek
Unnatural cyclic α-amino acids play an important role in the search for biologically active compounds and macromolecules. Enantiomers of natural amino acids with a D configuration are not naturally encoded, but can be chemically synthesized. The crystal structures of two enantiomers obtained by a method of stereoselective synthesis, namely (5R,8S)-8-tert-butyl-7-methoxy-8-methyl-9-oxa-6-azaspiro[4.5]decane-2,10-dione, (1), and (5S,8R)-8-tert-butyl-7-methoxy-8-methyl-9-oxa-6-azaspiro[4.5]decane-2,10-dione, (2), both C14H21NO4, were determined by X-ray diffraction...
July 1, 2017: Acta Crystallographica. Section C, Structural Chemistry
Paulina Kasperkiewicz, Yoav Altman, Maximiliano D'Angelo, Guy S Salvesen, Marcin Drag
Neutrophils, the front line defenders against infection, express four serine proteases (NSPs) that play roles in the control of cell-signaling pathways and defense against pathogens and whose imbalance leads to pathological conditions. Dissecting the roles of individual NSPs in humans is problematic because neutrophils are end-stage cells with a short half-life and minimal ongoing protein synthesis. To gain insight into the regulation of NSP activity we have generated a small-molecule chemical toolbox consisting of activity-based probes with different fluorophore-detecting groups with minimal wavelength overlap and highly selective natural and unnatural amino acid recognition sequences...
July 18, 2017: Journal of the American Chemical Society
Esben J Bjerrum, Jan H Jensen, Jakob L Tolborg
The isoelectric point of a peptide is a physicochemical property that can be accurately predicted from the sequence of the peptide when the peptide is built from natural amino acids. Peptides can however have chemical modifications, such as phosphorylations, amidations, and unnatural amino acids, which can result in erroneous predictions if not accounted for. Here we report on an open source program, pICalculax, which in an extensible way can handle pI calculations of modified peptides. Tests on a database of modified peptides and experimentally determined pI values show an improvement in pI predictions when taking the modifications into account...
July 21, 2017: Journal of Chemical Information and Modeling
Jihe Liu, James Hemphill, Subhas Samanta, Michael Tsang, Alexander Deiters
Site-specific incorporation of unnatural amino acids into proteins provides a powerful tool to study protein function. Here we report genetic code expansion in zebrafish embryos and its application to the optogenetic control of cell signaling. We genetically encoded four unnatural amino acids with a diverse set of functional groups, which included a photocaged lysine that was applied to the light-activation of luciferase and kinase activity. This approach enables versatile manipulation of protein function in live zebrafish embryos, a transparent and commonly used model organism to study embryonic development...
June 28, 2017: Journal of the American Chemical Society
Nadarajan Saravanan Prabhu, Hyungdon Yun
Photo-induced covalent crosslinking has emerged as the powerful strategy for analyzing and characterizing the protein-protein interaction and mapping protein 3D conformations. In the last decades, a number of photocrosslinking amino acids have been reported but only a few have been efficiently utilized for photocrosslinking purposes. Recently, incorporation of diazirine containing photoactivatable analogs such as photo-methionine, photo-leucine, photo-isoleucine and photo-lysine into target proteins were accomplished in live cells (Human A549cells, HEK 293) by depleting corresponding natural amino acid and supplementing these analogs in the medium...
June 8, 2017: Journal of Molecular Graphics & Modelling
Filip Liebsch, Mark R P Aurousseau, Tobias Bethge, Hugo McGuire, Silvia Scolari, Andreas Herrmann, Rikard Blunck, Derek Bowie, Gerd Multhaup
The β-secretase (BACE1) initiates processing of the amyloid precursor protein (APP) into Aβ peptides, which have been implicated as central players in the pathology of Alzheimer disease. BACE1 has been described as a copper-binding protein and its oligomeric state as being monomeric, dimeric, and/or multimeric, but the native cellular stoichiometry has remained elusive. Here, by using single-molecule fluorescence and in vitro cross-linking experiments with photo-activatable unnatural amino acids, we show that full-length BACE1, independently of its subcellular localization, exists as trimers in human cells...
August 11, 2017: Journal of Biological Chemistry
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