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Haruna Yata, Takumi Noguchi
Photosynthetic water oxidation is performed at the Mn4CaO5 cluster in photosystem II. In this study, we investigated the effect of methanol, an analogue of water, on the water oxidation reaction and its interaction site using Fourier transform infrared (FTIR) difference and time-resolved infrared (TRIR) spectroscopies. Flash-induced FTIR difference measurement of the S-state cycle showed that methanol decreases mainly the efficiency of the S3→S0 transition. TRIR measurement further showed that methanol slowed the rates of the S2→S3 and S3→S0 transitions...
July 17, 2018: Biochemistry
Keisuke Kawashima, Keisuke Saito, Hiroshi Ishikita
In photosystem II (PSII), redox-active tyrosine Z (TyrZ) forms a low-barrier H-bond with Nε of D1-His190. The PSII crystal structures show that Nδ of D1-His190 donates an H-bond to the carbonyl O of D1-Asn298. However, at a level of ~2 Å resolutions, a clear discrimination between the -NH2 and -C=O of the asparagine side-chain may not be possible based on the electron density map. Using quantum mechanical/molecular mechanical calculations, we investigated energetics of the D1-Asn298 conformations. In the D1-Asn298-rotated conformation, where the amide N group donates an H-bond to the deprotonated Nδ of D1-His190, oxidation of S2 resulted in formation of a neutral radical, either TyrZ• or D1-His190•...
July 17, 2018: Biochemistry
Giuseppina Turturici, Veronica La Fiora, Alessio Terenzi, Giampaolo Barone, Vincenzo Cavalieri
The G-quadruplex (G4) is a four-stranded DNA structure identified in vivo in guanine-rich regions located in the promoter of a number of genes. Intriguing evidence suggested that small molecules acting as G4-targeting ligands could potentially regulate multiple cellular processes via either stabilizing or disruptive effects on G4 motifs. Research in this field aims to prove the direct role of G4 ligands and/or structures on a specific biological process in a complex living organism. In this study, we evaluate in vivo the effects of a nickel(II)-salnaphen-like complex, named Nisaln, a potent G4 binder and stabilizer, during embryogenesis of the sea urchin embryo...
July 17, 2018: Biochemistry
Bin Zhao, Allison L Arnold, Marcelle A Coronel, Joyce H Lee, Taekyu Lee, Edward T Olejniczak, Stephen W Fesik
In order to test for on target toxicity of a new chemical entity, it is important to have comparable binding affinity of the compound in the target proteins from humans and the test species. To evaluate our Mcl-1 inhibitors, we tested them against rodent Mcl-1 and found a significant loss in binding affinity when compared to human Mcl-1. To understand the affinity loss, we used sequence alignments and structures of human Mcl-1/inhibitor complexes to identify the important differences in the amino acid sequences...
July 16, 2018: Biochemistry
Ross D Milton, John C Ruth, Jorg Deutzmann, Alfred M Spormann
Hydrogenotrophic methanogens oxidize molecular hydrogen to reduce carbon dioxide to methane. In methanogens without cytochromes, the initial endergonic reduction of CO2 to formylmethanofuran with H2-derived electrons is coupled to the ex-ergonic reduction of a heterodisulfide of coenzymes B and M, by flavin-based electron bifurcation (FBEB). In Methanococ-cus maripaludis, FBEB is performed by a heterodisulfide reductase (Hdr) enzyme complex that involves hydrogenase (Vhu), although formate dehydrogenase (Fdh) has been proposed as an alternative to Vhu...
July 16, 2018: Biochemistry
Shusuke Sato, Akimasa Miyanaga, Seung-Young Kim, Tomohisa Kuzuyama, Fumitaka Kudo, Tadashi Eguchi
In fosfomycin biosynthesis, the hydrolysis of cy-tidylyl (S)-2-hydroxypropylphosphonate ((S)-HPP-CMP) to afford (S)-HPP is the only uncharac-terized step. Since FomD is an uncharacterized pro-tein with a DUF402 domain that is encoded in the fosfomycin biosynthetic gene cluster, FomD was hypothesized to be responsible for this reaction. In the present study, FomD was found to hydrolyze (S)-HPP-CMP to give (S)-HPP and CMP efficiently in the presence of Mn2+ or Co2+. FomD also hydro-lyzed cytidylyl 2-hydroxyethylphosphonate (HEP-CMP), which is a biosynthetic intermediate before C-methylation...
July 16, 2018: Biochemistry
Christopher J Wilson, Madhurima Das, Shobini Jayaraman, Olga Gursky, John R Engen
Plasma high-density lipoproteins (HDLs) are protein-lipid nanoparticles that transport lipids and protect against atherosclerosis. Human apolipoprotein A-I (apoA-I) is the principal HDL protein whose mutations can cause either aberrant lipid metabolism or amyloid disease. Hydrogen-deuterium exchange (HDX) mass spectrometry (MS) was used to study the apoA-I conformation in model discoidal lipoproteins similar in size to large plasma HDL. We examined how point mutations associated with hereditary amyloidosis (F71Y and L170P) or atherosclerosis (L159R) influence the local apoA-I conformation in model lipoproteins...
July 13, 2018: Biochemistry
John Simms, Romez Uddin, Thomas P Sakmar, Joseph J Gingell, Michael L Garelja, Debbie L Hay, Margaret A Brimble, Paul W R Harris, Christopher Arthur Reynolds, David R Poyner
Calcitonin gene-related peptide (CGRP) binds to the complex of the calcitonin receptor-like receptor (CLR) with receptor activity-modifying protein 1 (RAMP1). It remains unclear how CGRP interacts with the transmembrane domain (including the extracellular loops) of this family B receptor. In the current study, a photoaffinity cross linker, p-azido L-phenylalanine (azF) was incorporated into CLR, chiefly in the second extracellular loop (ECL2) using genetic code expansion and unnatural amino acid mutagenesis...
July 13, 2018: Biochemistry
Steven K Albanese, Daniel L Parton, Mehtap Isik, Lucelenie Rodríguez-Laureano, Sonya M Hanson, Julie M Behr, Scott Gradia, Chris Jeans, Nicholas M Levinson, Markus A Seeliger, John Damon Chodera
Kinases play a critical role in many cellular signaling pathways and are dysregulated in a number of diseases, such as cancer, diabetes, and neurodegeneration. Since the FDA approval of imatinib in 2001, therapeutics targeting kinases now account for roughly 50% of current cancer drug discovery efforts. The ability to explore human kinase biochemistry, biophysics, and structural biology in the laboratory is essential to making rapid progress in understanding kinase regulation, designing selective inhibitors, and studying the emergence of drug resistance...
July 13, 2018: Biochemistry
Benjamin Selmke, Peter P Borbat, Chen Nickolaus, Raghavan Varadarajan, Jack H Freed, Wolfgang E Trommer
An intensively investigated intermediate state of protein folding is the molten globule state (MG), which contains secondary but hardly any tertiary structure. In previous work we have determined the distances between interacting spins within maltose binding protein (MBP) in its native state using continuous wave and double electron-electron resonance (DEER) EPR spectroscopy. Seven double mutants, MBP01 to MBP07, had been employed to investigate the structure within the two domains of MBP. DEER data nicely corroborated the previously available X-ray data...
July 13, 2018: Biochemistry
Lazaros Stefanidis, Nicholas D Fusco, Samantha E Cooper, Jillian Smith-Carpenter, Benjamin J Alper
Insulin-degrading enzyme (IDE) is a 110 kDa chambered zinc metalloendopeptidase that degrades insulin, amyloid beta, and other intermediate-sized aggregation prone peptides that adopt β-structures. Structural studies of IDE in complex with multiple physiological substrates have suggested a role for hydrophobic and aromatic residues of the IDE active site in substrate binding and catalysis. Here, we examine functional requirements for conserved hydrophobic and aromatic IDE active site residues that are positioned within 4...
July 13, 2018: Biochemistry
Jie Zhou, Xuewen Du, Xiaoyi Chen, Bing Xu
Despite the well-established biophysical principle of adhesion-guided in vitro morphogenesis, there are few single syn-thetic molecular species that can rapidly enable morphogenesis (e.g., a cell monolayer to cell spheroids) in cell culture because adhesion process inherently involves many signals. Here we show the use of adaptive multifunctional supramo-lecular assemblies of glycopeptides, consisting of cell adhesion sequence and saccharide, to induce cell spheroids rapid-ly from a monolayer of cells. Having a general architecture of N-terminal capping, glycosylation, and an integrin bind-ing sequence, the glycopeptides self-assemble to form a dynamic continuum of nanostructures (i...
July 12, 2018: Biochemistry
Jagannathan Alagurajan, Navjot Singh Athwal, Mark Scott Hargrove
Phytoglobins are plant hexacoordinate hemoglobins with reversible coordination of a histidine side chain to the ligand binding site of the heme iron. They mediate electron transfer reactions such as nitric oxide scavenging and are particularly efficient at reducing nitrite and hydroxylamine. Previous work with phytoglobins has focused only on single-turnovers of these reactions and have not revealed whether structural features, such as histidine hexacoordination, play a prominent role in the complete catalytic cycle...
July 12, 2018: Biochemistry
Qiansen Zhang, Mang Zhou, Lifen Zhao, Hualiang Jiang, Huaiyu Yang
G protein-coupled receptors (GPCRs) are the largest family of drug targets. The second extracellular loop (ECL2) and extracellular end of the third transmembrane helix (TM3) are basic structural elements of the GPCR ligand binding site. Currently, the disulphide bond between the two conserved cysteines in the ECL2 and TM3 is considered to be a basic GPCR structural feature. This disulphide bond has a significant effect on receptor dynamics and ligand binding. Here, molecular dynamics (MD) simulations and experimental results show that the two cysteines are distant from one another in the highest population conformational state of ligand-free class A GPCRs and do not form a disulphide bond, indicating that the dynamics of the GPCR extracellular side are different from our conventional understanding...
July 12, 2018: Biochemistry
Bing Wang, Yelu Shi, Jesus Tejero, Samantha M Powell, Leonard M Thomas, Mark T Gladwin, Sruti Shiva, Yong Zhang, George B Richter-Addo
The globular dioxygen-binding heme protein myoglobin (Mb) is present in several species. Its interactions with the simple nitrogen oxides, namely nitric oxide (NO) and nitrite, have been known for decades, but the physiological relevance has only recently become more fully appreciated. We previously reported the O-nitrito binding mode of nitrite to ferric horse heart wild-type (wt) MbIII and human hemoglobin. We have expanded on this work and report the interactions of nitrite with wt sperm whale (sw) Mb and its H64A, H64Q and V68A/I107Y mutants whose dissociation constants increase in the order H64Q < wt < V68A/I107Y < H64A...
July 12, 2018: Biochemistry
Burcu B Minsky, Rinat R Abzalimov, Chendi Niu, Yunlong Zhao, Zachary Kirsch, Paul L Dubin, Sergey N Savinov, Igor A Kaltashov
Inhibition of factor Xa (fXa) by antithrombin (AT) enabled by heparin or heparan sulfate is critical for controlling blood coagulation. AT activation by heparin had been investigated extensively, while heparin interaction with the trapped AT/fXa intermediates received relatively little attention. We use native electrospray ionization mass spectrometry to study the role of heparin chains of varying length (hexa-, octa-, deca- and eicosa-saccharides; dp6, dp8, dp10 and dp20) in AT/fXa complexes assembly. Despite being critical promoters of the AT/Xa binding, shorter heparin chains are excluded from the final products (trapped intermediates)...
July 12, 2018: Biochemistry
Andrew P Collins, Peter Anderson
Intrinsically disordered proteins (IDPs) are a large class of proteins that lack stable structures in solution, existing instead as dynamic conformational ensembles. To perform their biological functions, many IDPs bind to other proteins or nucleic acids. Although IDPs are unstructured in solution, when they interact with binding partners they fold into defined three-dimensional structures via coupled binding-folding processes. Since it frequently underlies IDP function, the mechanisms of this coupled binding-folding process are of great interest...
July 10, 2018: Biochemistry
Timo Fettweiss, Katrin Röllen, Joachim Granzin, Oliver Reiners, Stephan Endres, Thomas Drepper, Dieter Willbold, Karl-Erich Jaeger, Renu Batra-Safferling, Ulrich Krauss
Light, oxygen, voltage (LOV) proteins, a ubiquitously distributed class of photoreceptors, regulate a wide variety of light-dependent physiological responses. Due to their modular architecture, LOV domains, i.e. the sensory domains of LOV photoreceptors, have been widely used for the construction of optogenetic tools. We recently described the structure and function of a short LOV protein (DsLOV) from the marine phototropic bacterium Dinoroseobacter shibae, for which, in contrast to other LOV photoreceptors, the dark state represents the physiologically relevant signaling state...
July 10, 2018: Biochemistry
Galina Pankratova, Donal Leech, Lo Gorton, Lars Hederstedt
Extracellular electron transfer (EET) in microbial cells is essential for certain biotechnological applications and contributes to the biogeochemical cycling of elements and syntrophic microbial metabolism in complex natural environments. The Gram-positive lactic acid bacterium Enterococcus faecalis, an opportunistic human pathogen, is shown to be able to transfer electrons generated in fermentation metabolism to electrodes directly and indirectly via mediators. By exploiting E. faecalis wild-type and mutant cells it is demonstrated that reduced demethylmenaquinone in the respiratory chain in the bacterial cytoplasmic membrane is crucial for the EET...
July 10, 2018: Biochemistry
Ko-Hsin Chin, Juin-Ming Liang, Jauo-Guey Yang, Min-Shao Shih, Zhi-Le Tu, Yu-Chuang Wang, Xing-Han Sun, Nien-Jen Hu, Zhao-Xun Liang, J Maxwell Dow, Robert P Ryan, Shan-Ho Chou
No abstract text is available yet for this article.
July 9, 2018: Biochemistry
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