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Biochemistry

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https://www.readbyqxmd.com/read/28448715/acyl-carrier-protein-cyanylation-delivers-a-ketoacyl-synthase-carrier-protein-crosslink
#1
Grace Thiele, Conne Friedman, Kathleen Tsai, Joris Beld, Casey H Londergan, Louise K Charkoudian
Acyl carrier proteins (ACPs) are central hubs in polyketide and fatty acid biosynthetic pathways, but the fast motions of the ACP's phosphosphopantetheine (Ppant) arm make its conformational dynamics difficult to capture using traditional spectroscopic approaches. Here we report that converting the terminal thiol of E. coli ACP's Ppant arm into a thiocyanate activates this site to form a selective crosslink with the active site cys-teine of its partner ketoacyl synthase (KS; FabF). The reaction releases a cyanide anion, which can be detected by infrared spectroscopy...
April 27, 2017: Biochemistry
https://www.readbyqxmd.com/read/28406291/using-ligand-induced-protein-chemical-shift-perturbations-to-determine-protein-ligand-structures
#2
Zhuoqin Yu, Pengfei Li, Kenneth M Merz
Protein chemical shift perturbations (CSPs), upon ligand binding, can be used to refine the structure of a protein-ligand complex by comparing experimental CSPs with calculated CSPs for any given set of structural coordinates. Herein, we describe a fast and accurate methodology that opens up new opportunities for improving the quality of protein-ligand complexes using nuclear magnetic resonance (NMR)-based approaches by focusing on the effect of the ligand on the protein. The new computational approach, (1)H empirical chemical shift perturbation (HECSP), has been developed to rapidly calculate ligand binding-induced (1)H CSPs in a protein...
April 27, 2017: Biochemistry
https://www.readbyqxmd.com/read/28445031/importance-of-loop-l1-dynamics-for-substrate-capture-and-catalysis-in-pseudomonas-aeruginosa-d-arginine-dehydrogenase
#3
Daniel Ouedraogo, Michael Souffrant, Sheena Vasquez, Donald Hamelberg, Giovanni Gadda
Mobile loops located at the active site entrance in enzymes often participate in conformational changes required to shield the reaction from bulk solvent, to control substrate access to the active site, and to position residues for substrate binding and catalysis. In D-arginine dehydrogenase from Pseudomonas aeruginosa (PaDADH) previous crystallographic data suggested that residues 45-47 in the FAD-binding domain and 50-56 in the substrate-binding domain in loop L1 could adopt two distinct conformations. In this study, we have used molecular dynamics, kinetics, and fluorescence spectroscopy on the S45A and A46G enzyme variants of PaDADH to investigate the impact of mutations of loop L1 on the catalytic function of the enzyme...
April 26, 2017: Biochemistry
https://www.readbyqxmd.com/read/28445027/structurally-linked-dynamics-in-lactate-dehydrogenases-of-evolutionarily-distinct-species
#4
Matthew J Varga, Michael W Dzierlenga, Steven D Schwartz
We present new findings on how primary and secondary structure affects the role of fast protein motions in the reaction coordinates of enzymatic reactions. Using transition path sam- pling (TPS) and committor distribution analysis, we examined the difference in the role of these fast protein motions in the reaction coordinate of lactate dehydrogenases (LDH) of Api- complexa organisms Plasmodium falciparum and Cryptosporidium parvum. Having evolved separately from a common malate dehydrogenase ancestor, there are several important struc- tural differences between the two enzymes, notably a five amino acid insertion into the active site loop of P...
April 26, 2017: Biochemistry
https://www.readbyqxmd.com/read/28443334/the-n-terminal-flanking-region-modulates-the-actin-binding-affinity-of-utrophin-tandem-calponin-homology-domain
#5
Surinder M Singh, Swati Bandi, Krishna M G Mallela
Despite sharing high sequence similarity, tandem calponin-homology (CH) domain of utrophin binds to actin 30 times stronger than that of dystrophin. We have previously shown that this difference in actin binding affinity could not be accounted by the differences in inter-CH-domain linkers (Bandi et al., Biochemistry, 54 (2015) 5480-5488). Here, we examined the role of the N-terminal flanking region. Utrophin tandem CH domain contains a 27-residue flanking region before its CH1 domain. We examined its effect by comparing the structure and function of full-length utrophin tandem CH domain Utr(1-261) and its truncated construct Utr(28-261)...
April 26, 2017: Biochemistry
https://www.readbyqxmd.com/read/28425697/conserved-helix-flanking-prolines-modulate-intrinsically-disordered-protein-target-affinity-by-altering-the-lifetime-of-the-bound-complex
#6
Michael D Crabtree, Wade Borcherds, Anusha Poosapati, Sarah L Shammas, Gary W Daughdrill, Jane Clarke
Appropriate integration of cellular signals requires a delicate balance of ligand-target binding affinities. Increasing the level of residual structure in intrinsically disordered proteins (IDPs), which are overrepresented in these cellular processes, has been shown previously to enhance binding affinities and alter cellular function. Conserved proline residues are commonly found flanking regions of IDPs that become helical upon interacting with a partner protein. Here, we mutate these helix-flanking prolines in p53 and MLL and find opposite effects on binding affinity upon an increase in free IDP helicity...
April 26, 2017: Biochemistry
https://www.readbyqxmd.com/read/28406021/the-nup62-coiled-coil-motif-provides-plasticity-for-triple-helix-bundle-formation
#7
Pravin S Dewangan, Parshuram J Sonawane, Ankita R Chouksey, Radha Chauhan
The central transport channel of the vertebrate nuclear pore complex (NPC) consists of nucleoporins: Nup62, Nup54, and Nup58. The coiled-coil domains in α-helical regions of these nucleoporins are thought to be crucial for several protein-protein interactions in the NPC subcomplexes. In this study, we determined the crystal structure of the coiled-coil domain of rat Nup62 fragment (residues 362-425) to 2.4 Å resolution. The crystal structure shows the conserved coiled-coil domain as a parallel three-helix bundle for the Nup62(362-425) fragment...
April 26, 2017: Biochemistry
https://www.readbyqxmd.com/read/28441502/differential-coupling-of-binding-atp-hydrolysis-and-transport-of-fluorescent-probes-with-p-glycoprotein-in-lipid-nanodiscs
#8
Mavis Jiarong Li, Abhinav Nath, William M Atkins
The ATP-binding cassette transporter P-glycoprotein (ABCB1) plays a major role in cellular resistance to drugs, and drug interactions. Experimental studies support a mechanism with nucleotide-dependent fluctuation between inward-facing and outward-facing conformations, which are coupled to nucleotide hydrolysis. However, detailed insight into drug-dependent modulation of these conformational ensembles is lacking. Different drugs likely occupy partially overlapping but distinct sites, and are therefore variably coupled to nucleotide binding and hydrolysis...
April 25, 2017: Biochemistry
https://www.readbyqxmd.com/read/28441492/caenorhabditis-elegans-prmt-7-and-prmt-9-are-evolutionarily-conserved-protein-arginine-methyltransferases-with-distinct-substrate-specificities
#9
Andrea Hadjikyriacou, Steven Gerard Clarke
Caenorhabditis elegans protein arginine methyltransferases PRMT-7 and PRMT-9 are two evolutionarily conserved enzymes, with distinct orthologs in plants, invertebrates, and vertebrates. Biochemical characterization of these two enzymes reveals that they share much in common with their mammalian orthologs. C. elegans PRMT-7 produces only monomethyl arginine (MMA) and preferentially methylates R-X-R motifs in a broad collection of substrates, including human histone peptides and RG-rich peptides. In addition, the activity of the PRMT-7 enzyme is dependent on temperature, the presence of metal ions, and the reducing agent dithiothreitol (DTT)...
April 25, 2017: Biochemistry
https://www.readbyqxmd.com/read/28441004/insights-into-the-mechanisms-by-which-clostridial-neurotoxins-discriminate-between-gangliosides
#10
Joshua R Burns, Gregory S Lambert, Michael R Baldwin
Botulinum neurotoxins (BoNTs) and Tetanus neurotoxin (TeNT) are the causative agents of the paralytic diseases botulism and tetanus, respectively. Entry of toxins into neurons is mediated through initial interactions with gangliosides, followed by binding to a protein co-receptor. Herein we aimed to understand the mechanism through which individual neurotoxins recognize the carbohydrate motif of gangliosides. Using cell-based and in vitro binding assays, in conjunction with structure-driven site directed mutagenesis, a conserved hydrophobic residue within the BoNTs that contributes to both affinity and specificity towards Sia5-containing gangliosides was identified...
April 25, 2017: Biochemistry
https://www.readbyqxmd.com/read/28346775/hyperinsulinism-causing-mutations-cause-multiple-molecular-defects-in-sur1-nbd1
#11
Claudia P Alvarez, Marijana Stagljar, D Ranjith Muhandiram, Voula Kanelis
The sulfonylurea receptor 1 (SUR1) protein forms the regulatory subunit in ATP sensitive K(+) (KATP) channels in the pancreas. SUR proteins are members of the ATP binding cassette (ABC) superfamily of proteins. Binding and hydrolysis of MgATP at the SUR nucleotide binding domains (NBDs) lead to channel opening. Pancreatic KATP channels play an important role in insulin secretion. SUR1 mutations that result in increased levels of channel opening ultimately inhibit insulin secretion and lead to neonatal diabetes...
April 25, 2017: Biochemistry
https://www.readbyqxmd.com/read/28437098/interaction-of-fibrin-with-the-very-low-density-lipoprotein-receptor-further-characterization-and-localization-of-the-vldl-receptor-binding-site-in-fibrin-%C3%AE-n-domains
#12
Sergiy Yakovlev, Leonid Medved
Our recent study revealed that fibrin and the VLDL receptor (VLDLR) interact with each other through a pair of fibrin βN-domains and CR domains of the receptor and this interaction promotes transendothelial migration of leukocytes and thereby inflammation. The major objectives of the present study were to further clarify the molecular mechanism of fibrin-VLDLR interaction and to identify amino acid residues in the βN-domains involved in this interaction. Our binding experiments with the (β15-66)2 fragment, which corresponds to a pair of fibrin βN-domains, and the VLDLR(1-8) fragment consisting of eight CR domains of VLDLR, revealed that interaction between them strongly depends on ionic strength and chemical modification of all Lys or Arg residues in (β15-66)2 results in abrogation of this interaction...
April 24, 2017: Biochemistry
https://www.readbyqxmd.com/read/28437073/inter-motif-communication-induces-hierarchical-ca2-filling-of-caldendrin
#13
Uday Kiran, Phanindranath Regur, Michael R Kreutz, Yogendra Sharma, Asima Chakraborty
A crucial event in calcium signalling is the transition of a calcium sensor from the apo (Ca2+ free) to the holo (Ca2+ saturated) state. Caldendrin (CDD) is a neuronal Ca2+-binding protein with two functional (EF3 and EF4) and two atypical (EF1 and EF2), non-Ca2+-binding EF-hand motifs. During the transition from the apo to the holo state, guided by the step-wise filling of Ca2+, the protein passes through distinct states and acquires a stable conformational state when only EF3 is occupied by Ca2+. This state is characterized by a Ca2+-derived structural gain in EF3 with destabilization of the EF4 motif...
April 24, 2017: Biochemistry
https://www.readbyqxmd.com/read/28437072/the-single-disulfide-directed-%C3%AE-hairpin-fold-dynamics-stability-and-engineering
#14
Balasubramanyam Chittoor, Krishnarjuna Bankala, Rodrigo A W Morales, Christopher Andrew MacRaild, Maiada Sadek, Eleanor Ww Leung, Samuel Robinson, Michael Pennington, Raymond S Norton
Grafting bioactive peptide sequences onto small cysteine-rich scaffolds is a promising strategy to enhance their stability and value in novel peptide-based therapeutics. However, correctly folded disulfide-rich peptides can be challenging to produce by either recombinant or synthetic means. The single disulfide-directed β-hairpin (SDH) fold, first observed in contryphan-Vc1, provides a potential alternative to complex disulfide-rich scaffolds. We have undertaken recombinant production of full-length contryphan-Vc1 (rCon-Vc1[Z1Q]) and a truncated analog (rCon-Vc11-22[Z1Q]), analyzed the backbone dynamics of rCon-Vc1[Z1Q], and probed the conformational and proteolytic stability of these peptides to evaluate the potential of contryphan-Vc1 as a molecular scaffold...
April 24, 2017: Biochemistry
https://www.readbyqxmd.com/read/28436221/the-iron-chaperone-protein-cyay-from-vibrio-cholerae-is-a-heme-binding-protein
#15
Takeshi Uchida, Noriyuki Kobayashi, Souichiro Muneta, Koichiro Ishimori
CyaY is an iron transport protein for Fe-S cluster biosynthetic systems and a ferrochelatase that catalyzes insertion of Fe(2+) into protoporphyrin IX. Here, we found that CyaY has the ability to bind heme as well as iron, exhibiting a dissociation constant for heme of 21 ± 6 nM. Absorption and resonance Raman spectra revealed that both ferric and ferrous forms of heme were bound to an anionic ligand (e.g., tyrosine and/or cysteine). Consistent with this, mutagenesis studies showed that Tyr67 and Cys78 are possible heme ligands of CyaY...
April 24, 2017: Biochemistry
https://www.readbyqxmd.com/read/28345933/structure-energy-relationships-of-halogen-bonds-in-proteins
#16
Matthew R Scholfield, Melissa Coates Ford, Anna-Carin C Carlsson, Hawera Butta, Ryan A Mehl, P Shing Ho
The structures and stabilities of proteins are defined by a series of weak noncovalent electrostatic, van der Waals, and hydrogen bond (HB) interactions. In this study, we have designed and engineered halogen bonds (XBs) site-specifically to study their structure-energy relationship in a model protein, T4 lysozyme. The evidence for XBs is the displacement of the aromatic side chain toward an oxygen acceptor, at distances that are equal to or less than the sums of their respective van der Waals radii, when the hydroxyl substituent of the wild-type tyrosine is replaced by a halogen...
April 22, 2017: Biochemistry
https://www.readbyqxmd.com/read/28430414/dynamic-and-energetic-signatures-of-adenine-tracts-in-a-ra-dt-rna-dna-hybrid-and-in-homologous-rna-dna-rna-rna-and-dna-dna-double-helices
#17
Yuegao Huang, Irina M Russu
Nuclear magnetic resonance spectroscopy and proton exchange are being used to characterize the opening reactions of individual base pairs in the RNA-DNA hybrid 5'-rGCGAUAAAAAGGCC-3'/5'-dGGCCTTTTTATCGC-3'. The hybrid contains a central tract of five rA-dT base pairs. The rates and the equilibrium constant of the opening reaction for each base pair are determined from the dependence of the exchange rates of imino protons on ammonia concentration, at 10°C. The results are compared to those previously obtained by our laboratory for three homologous duplexes of the same base sequence (except for the appropriate T/U substitution), containing tracts of dA-rU, rA-rU or dA-dT base pairs...
April 21, 2017: Biochemistry
https://www.readbyqxmd.com/read/28429932/thermodynamics-of-the-thermal-denaturation-of-acid-molten-globule-state-of-cytochrome-c-indicate-a-reversible-high-temperature-oligomerization-process
#18
Shigeyoshi Nakamura, Tomonori Saotome, Akiko Nakazawa, Masao Fukuda, Yutaka Kuroda, Shun-Ichi Kidokoro
In this study, we performed differential scanning calorimetry (DSC) and pressure perturbation calorimetry (PPC) analysis of the thermal transition of cytochrome c from an acidic molten globule (MG) state with the protein concentrations of 0.5-18.2 mg/mL. DSC profiles were highly reversible and showed clear protein-concentration dependence, indicating that reversible oligomerization occurred accompanying the thermal transition from the MG state. The DSC and PPC data required at least a six-state model including three new oligomeric states: dimer (I2), trimer (I3), and tetramer (I4) in addition to the three monomeric states previously characterized...
April 21, 2017: Biochemistry
https://www.readbyqxmd.com/read/28406615/redox-sensitive-marr-homologue-bifr-from-burkholderia-thailandensis-regulates-biofilm-formation
#19
Ashish Gupta, Stanley M Fuentes, Anne Grove
Biofilm formation by pathogenic Burkholderia species is a serious complication as it renders the bacteria resistant to antibiotics and host defenses. Using B. thailandensis, we report here a novel redox-sensitive member of the multiple antibiotic resistance regulator (MarR) protein family, BifR, which represses biofilm formation. BifR is encoded as part of the emrB-bifR operon; emrB-bifR is divergent to ecsC, which encodes a putative LasA protease. In Pseudomonas aeruginosa, LasA has been implicated in virulence by contributing to cleavage of elastase...
April 21, 2017: Biochemistry
https://www.readbyqxmd.com/read/28402104/hydrogen-deuterium-exchange-mass-spectrometry-of-human-green-opsin-reveals-a-conserved-pro-pro-motif-in-extracellular-loop-2-of-monostable-visual-g-protein-coupled-receptors
#20
Lukas Hofmann, Nathan S Alexander, Wenyu Sun, Jianye Zhang, Tivadar Orban, Krzysztof Palczewski
Opsins comprise the protein component of light sensitive G protein-coupled receptors (GPCRs) in the retina of the eye that are responsible for the transduction of light into a biochemical signal. Here, we used hydrogen/deuterium (H/D) exchange coupled with mass spectrometry to map conformational changes in green cone opsin upon light activation. We then compared these findings with those reported for rhodopsin. The extent of H/D exchange in green cone opsin was greater than in rhodopsin in the dark and bleached states, suggesting a higher structural heterogeneity for green cone opsin...
April 21, 2017: Biochemistry
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