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https://www.readbyqxmd.com/read/28089449/transferase-versus-hydrolase-the-role-of-conformational-flexibility-in-reaction-specificity
#1
Samuel H Light, Laty A Cahoon, Kiran V Mahasenan, Mijoon Lee, Bill Boggess, Andrei S Halavaty, Shahriar Mobashery, Nancy E Freitag, Wayne F Anderson
Active in the aqueous cellular environment where a massive excess of water is perpetually present, enzymes that catalyze the transfer of an electrophile to a non-water nucleophile (transferases) require specific strategies to inhibit mechanistically related hydrolysis reactions. To identify principles that confer transferase versus hydrolase reaction specificity, we exploited two enzymes that use highly similar catalytic apparatuses to catalyze the transglycosylation (a transferase reaction) or hydrolysis of α-1,3-glucan linkages in the cyclic tetrasaccharide cycloalternan (CA)...
January 5, 2017: Structure
https://www.readbyqxmd.com/read/28089451/crystallogenesis-of-membrane-proteins-mediated-by-polymer-bounded-lipid-nanodiscs
#2
Jana Broecker, Bryan T Eger, Oliver P Ernst
For some membrane proteins, detergent-mediated solubilization compromises protein stability and functionality, often impairing biophysical and structural analyses. Hence, membrane-protein structure determination is a continuing bottleneck in the field of protein crystallography. Here, as an alternative to approaches mediated by conventional detergents, we report the crystallogenesis of a recombinantly produced membrane protein that never left a lipid bilayer environment. We used styrene-maleic acid (SMA) copolymers to solubilize lipid-embedded proteins into SMA nanodiscs, purified these discs by affinity and size-exclusion chromatography, and transferred proteins into the lipidic cubic phase (LCP) for in meso crystallization...
January 3, 2017: Structure
https://www.readbyqxmd.com/read/28089452/co-folding-of-a-flif-flig-split-domain-forms-the-basis-of-the-ms-c-ring-interface-within-the-bacterial-flagellar-motor
#3
Michael J Lynch, Robert Levenson, Eun A Kim, Ria Sircar, David F Blair, Frederick W Dahlquist, Brian R Crane
The interface between the membrane (MS) and cytoplasmic (C) rings of the bacterial flagellar motor couples torque generation to rotation within the membrane. The structure of the C-terminal helices of the integral membrane protein FliF (FliFC) bound to the N terminal domain of the switch complex protein FliG (FliGN) reveals that FliGN folds around FliFC to produce a topology that closely resembles both the middle and C-terminal domains of FliG. The interface is consistent with solution-state nuclear magnetic resonance, small-angle X-ray scattering, in vivo interaction studies, and cellular motility assays...
December 31, 2016: Structure
https://www.readbyqxmd.com/read/28089450/a-structural-model-for-vinculin-insertion-into-pip2-containing-membranes-and-the-effect-of-insertion-on-vinculin-activation-and-localization
#4
Peter M Thompson, Srinivas Ramachandran, Lindsay B Case, Caitlin E Tolbert, Arpit Tandon, Mihir Pershad, Nikolay V Dokholyan, Clare M Waterman, Sharon L Campbell
Vinculin, a scaffolding protein that localizes to focal adhesions (FAs) and adherens junctions, links the actin cytoskeleton to the adhesive super-structure. While vinculin binds to a number of cytoskeletal proteins, it can also associate with phosphatidylinositol 4,5-bisphosphate (PIP2) to drive membrane association. To generate a structural model for PIP2-dependent interaction of vinculin with the lipid bilayer, we conducted lipid-association, nuclear magnetic resonance, and computational modeling experiments...
December 31, 2016: Structure
https://www.readbyqxmd.com/read/28065506/cryoelectron-microscopy-maps-of-human-papillomavirus-16-reveal-l2-densities-and-heparin-binding-site
#5
Jian Guan, Stephanie M Bywaters, Sarah A Brendle, Robert E Ashley, Alexander M Makhov, James F Conway, Neil D Christensen, Susan Hafenstein
Human papillomavirus (HPV) is a significant health burden and leading cause of virus-induced cancers. The current commercial vaccines are genotype specific and provide little therapeutic benefit to patients with existing HPV infections. Host entry mechanisms represent an excellent target for alternative therapeutics, but HPV receptor use, the details of cell attachment, and host entry are inadequately understood. Here we present near-atomic resolution structures of the HPV16 capsid and HPV16 in complex with heparin, both determined from cryoelectron micrographs collected with direct electron detection technology...
December 31, 2016: Structure
https://www.readbyqxmd.com/read/28089448/structural-basis-for-the-interaction-of-a-human-small-heat-shock-protein-with-the-14-3-3-universal-signaling-regulator
#6
Nikolai N Sluchanko, Steven Beelen, Alexandra A Kulikova, Stephen D Weeks, Alfred A Antson, Nikolai B Gusev, Sergei V Strelkov
By interacting with hundreds of protein partners, 14-3-3 proteins coordinate vital cellular processes. Phosphorylation of the small heat shock protein, HSPB6, within its intrinsically disordered N-terminal domain activates its interaction with 14-3-3, ultimately triggering smooth muscle relaxation. After analyzing the binding of an HSPB6-derived phosphopeptide to 14-3-3 using isothermal calorimetry and X-ray crystallography, we have determined the crystal structure of the complete assembly consisting of the 14-3-3 dimer and full-length HSPB6 dimer and further characterized this complex in solution using fluorescence spectroscopy, small-angle X-ray scattering, and limited proteolysis...
December 30, 2016: Structure
https://www.readbyqxmd.com/read/28089447/networks-of-dynamic-allostery-regulate-enzyme-function
#7
Michael Joseph Holliday, Carlo Camilloni, Geoffrey Stuart Armstrong, Michele Vendruscolo, Elan Zohar Eisenmesser
Many protein systems rely on coupled dynamic networks to allosterically regulate function. However, the broad conformational space sampled by non-coherently dynamic systems has precluded detailed analysis of their communication mechanisms. Here, we have developed a methodology that combines the high sensitivity afforded by nuclear magnetic resonance relaxation techniques and single-site multiple mutations, termed RASSMM, to identify two allosterically coupled dynamic networks within the non-coherently dynamic enzyme cyclophilin A...
December 27, 2016: Structure
https://www.readbyqxmd.com/read/28089446/stk40-is-a-pseudokinase-that-binds-the-e3%C3%A2-ubiquitin-ligase-cop1
#8
Izabela Durzynska, Xiang Xu, Guillaume Adelmant, Scott B Ficarro, Jarrod A Marto, Piotrek Sliz, Sacha Uljon, Stephen C Blacklow
Serine/threonine kinase 40 (STK40) was originally identified as a distant homolog of Tribbles-family proteins. Despite accumulating data attesting to the importance of STK40 in a variety of different physiologic processes, little is known about its biological activity or mechanism of action. Here, we show that STK40 interacts with Constitutive Photomorphogenic Protein 1 (COP1), relying primarily on a C-terminal sequence analogous to the motif found in Tribbles proteins. In order to further elucidate structure-function relationships in STK40, we determined the crystal structure of the STK40 kinase homology domain at 2...
December 24, 2016: Structure
https://www.readbyqxmd.com/read/28065508/kobuviral-non-structural-3a-proteins-act-as-molecular-harnesses-to-hijack-the-host-acbd3-protein
#9
Martin Klima, Dominika Chalupska, Bartosz Różycki, Jana Humpolickova, Lenka Rezabkova, Jan Silhan, Adriana Baumlova, Anna Dubankova, Evzen Boura
Picornaviruses are small positive-sense single-stranded RNA viruses that include many important human pathogens. Within the host cell, they replicate at specific replication sites called replication organelles. To create this membrane platform, they hijack several host factors including the acyl-CoA-binding domain-containing protein-3 (ACBD3). Here, we present a structural characterization of the molecular complexes formed by the non-structural 3A proteins from two species of the Kobuvirus genus of the Picornaviridae family and the 3A-binding domain of the host ACBD3 protein...
December 21, 2016: Structure
https://www.readbyqxmd.com/read/28065507/crystal-structure-of-4-6-%C3%AE-glucanotransferase-supports-diet-driven-evolution-of-gh70-enzymes-from-%C3%AE-amylases-in-oral-bacteria
#10
Yuxiang Bai, Joana Gangoiti, Bauke W Dijkstra, Lubbert Dijkhuizen, Tjaard Pijning
Food processing and refining has dramatically changed the human diet, but little is known about whether this affected the evolution of enzymes in human microbiota. We present evidence that glycoside hydrolase family 70 (GH70) glucansucrases from lactobacilli, synthesizing α-glucan-type extracellular polysaccharides from sucrose, likely evolved from GH13 starch-acting α-amylases, via GH70 4,6-α-glucanotransferases. The crystal structure of a 4,6-α-glucanotransferase explains the mode of action and unique product specificity of these enzymes...
December 21, 2016: Structure
https://www.readbyqxmd.com/read/28065505/atp-induced-structural-remodeling-in-the-antiactivator-flen-enables-formation-of-the-functional-dimeric-form
#11
Chanchal, Priyajit Banerjee, Deepti Jain
FleN, a P loop ATPase is vital for maintaining a monotrichous phenotype in Pseudomonas aeruginosa. FleN exhibits antagonistic activity against FleQ, the master transcriptional regulator of flagellar genes. Crystal structures of FleN in the apo form (1.66 Å) and in complex with β,γ-imidoadenosine 5'-triphosphate (1.55 Å) reveal that it undergoes drastic conformational changes on ATP binding to attain a structure capable of dimerization. Mutations of the residues that stabilize the binding of ATP were defective in their ability to dimerize and do not inhibit ATP hydrolysis by FleQ...
December 21, 2016: Structure
https://www.readbyqxmd.com/read/28017522/structural-basis-for-ligand-binding-to-the-guanidine-i-riboswitch
#12
Caroline W Reiss, Yong Xiong, Scott A Strobel
The guanidine-I riboswitch is a conserved RNA element with approximately 2,000 known examples across four phyla of bacteria. It exists upstream of nitrogen metabolism and multidrug resistance transporter genes and alters expression through the specific recognition of a free guanidinium cation. Here we report the structure of a guanidine riboswitch aptamer from Sulfobacillus acidophilus at 2.7 Å resolution. Helices P1, P1a, P1b, and P2 form a coaxial stack that acts as a scaffold for ligand binding. A previously unidentified P3 helix docks into P1a to form the guanidinium binding pocket, which is completely enclosed...
December 18, 2016: Structure
https://www.readbyqxmd.com/read/28017521/the-ciliopathy-associated-cep104-protein-interacts-with-tubulin-and-nek1-kinase
#13
Caezar Al-Jassar, Antonina Andreeva, Deepak D Barnabas, Stephen H McLaughlin, Christopher M Johnson, Minmin Yu, Mark van Breugel
Cilia are thin cell projections with essential roles in cell motility, fluid movement, sensing, and signaling. They are templated from centrioles that dock against the plasma membrane and subsequently extend their peripheral microtubule array. The molecular mechanisms underpinning cilia assembly are incompletely understood. Cep104 is a key factor involved in cilia formation and length regulation that rides on the ends of elongating and shrinking cilia. It is mutated in Joubert syndrome, a genetically heterogeneous ciliopathy...
December 18, 2016: Structure
https://www.readbyqxmd.com/read/27989621/binding-of-myomesin-to-obscurin-like-1-at-the-muscle-m-band-provides-a-strategy-for-isoform-specific-mechanical-protection
#14
Stefano Pernigo, Atsushi Fukuzawa, Amy E M Beedle, Mark Holt, Adam Round, Alessandro Pandini, Sergi Garcia-Manyes, Mathias Gautel, Roberto A Steiner
The sarcomeric cytoskeleton is a network of modular proteins that integrate mechanical and signaling roles. Obscurin, or its homolog obscurin-like-1, bridges the giant ruler titin and the myosin crosslinker myomesin at the M-band. Yet, the molecular mechanisms underlying the physical obscurin(-like-1):myomesin connection, important for mechanical integrity of the M-band, remained elusive. Here, using a combination of structural, cellular, and single-molecule force spectroscopy techniques, we decode the architectural and functional determinants defining the obscurin(-like-1):myomesin complex...
December 15, 2016: Structure
https://www.readbyqxmd.com/read/27989622/the-molecular-basis-of-aichi-virus-3a-protein-activation-of-phosphatidylinositol-4-kinase-iii%C3%AE-pi4kb-through-acbd3
#15
Jacob A McPhail, Erik H Ottosen, Meredith L Jenkins, John E Burke
Phosphatidylinositol 4-kinase III beta (PI4KIIIβ) is an essential enzyme in mediating membrane transport, and plays key roles in facilitating viral infection. Many pathogenic positive-sense single-stranded RNA viruses activate PI4KIIIβ to generate phosphatidylinositol 4-phosphate (PI4P)-enriched organelles for viral replication. The molecular basis for PI4KIIIβ activation during viral infection has remained largely unclear. We describe the biochemical reconstitution and characterization of the complex of PI4KIIIβ with the Golgi protein Acyl-coenzyme A binding domain containing protein 3 (ACBD3) and Aichi virus 3A protein on membranes...
December 7, 2016: Structure
https://www.readbyqxmd.com/read/27939783/structural-basis-for-regulation-and-specificity-of-fructooligosaccharide-import-in-streptococcus-pneumoniae
#16
Simone Culurgioni, Gemma Harris, Anirudh K Singh, Samantha J King, Martin A Walsh
Streptococcus pneumoniae is dependent on carbohydrate uptake for colonization and pathogenesis, and dedicates over a third of its transport systems to their uptake. The ability of the pneumococcus to utilize fructooligosaccharides (FOSs) is attributed to the presence of one of two types of FOS ATP-binding cassette (ABC) transporters. Strains encoding SfuABC are only able to utilize short-chain FOSs, while strains encoding FusABC can utilize both short- and long-chain FOSs. The crystal structures of the substrate-binding protein FusA in its open and closed conformations bound to FOSs, and solution scattering data of SfuA, delineate the structural basis for import of short- and long-chain FOSs...
December 7, 2016: Structure
https://www.readbyqxmd.com/read/27916521/structural-insights-into-linear-tri-ubiquitin-recognition-by-a20-binding-inhibitor-of-nf-%C3%AE%C2%BAb-abin-2
#17
Shan-Meng Lin, Su-Chang Lin, Jhen-Yi Hong, Tsung-Wei Su, Bai-Jiun Kuo, Wei-Hsin Chang, Yi-Fan Tu, Yu-Chih Lo
Recognition of linear polyubiquitin by specific ubiquitin-binding proteins plays an important role in mediating nuclear factor-κB (NF-κB) signaling. A20 binding proteins, ABINs, recognize linear polyubiquitin and A20 through UBAN and AHD1, respectively, for the inhibition of NF-κB activation. Here we report the crystal structure of the AHD1-UBAN fragment of ABIN2 in complex with linear tri-ubiquitin, which reveals a 2:1 stoichiometry of the complex. Structural analyses together with mutagenesis, pull-down, and isothermal titration calorimetry assays show that the hABIN2:tri-ubiquitin interaction is mainly through the primary ubiquitin-binding site, and also through the secondary ubiquitin-binding site under a high local protein concentration...
November 24, 2016: Structure
https://www.readbyqxmd.com/read/27916520/water-bridge-mediates-recognition-of-mrna-cap-in-eif4e
#18
Dilraj Lama, Mohan R Pradhan, Christopher J Brown, Rohan S Eapen, Thomas L Joseph, Chee-Keong Kwoh, David P Lane, Chandra S Verma
Ligand binding pockets in proteins contain water molecules, which play important roles in modulating protein-ligand interactions. Available crystallographic data for the 5' mRNA cap-binding pocket of the translation initiation factor protein eIF4E shows several structurally conserved waters, which also persist in molecular dynamics simulations. These waters engage an intricate hydrogen-bond network between the cap and protein. Two crystallographic waters in the cleft of the pocket show a high degree of conservation and bridge two residues, which are part of an evolutionarily conserved scaffold...
November 24, 2016: Structure
https://www.readbyqxmd.com/read/27889207/dual-site-phosphorylation-of-caspase-7-by-pak2-blocks-apoptotic-activity-by-two-distinct-mechanisms
#19
Scott J Eron, Kishore Raghupathi, Jeanne A Hardy
Caspases, the cysteine proteases that execute apoptosis, are tightly regulated via phosphorylation by a series of kinases. Although all apoptotic caspases work in concert to promote apoptosis, different kinases regulate individual caspases. Several sites of caspase-7 phosphorylation have been reported, but without knowing the molecular details, it has been impossible to exploit or control these complex interactions, which normally prevent unwanted proliferation. During dysregulation, PAK2 kinase plays an alternative anti-apoptotic role, phosphorylating caspase-7 and promoting unfettered cell growth and chemotherapeutic resistance...
November 22, 2016: Structure
https://www.readbyqxmd.com/read/27916518/mechanism-of-structural-tuning-of-the-hepatitis-c-virus-human-cellular-receptor-cd81-large-extracellular-loop
#20
Eva S Cunha, Pedro Sfriso, Adriana L Rojas, Adam Hospital, Modesto Orozco, Nicola G A Abrescia
Hepatitis C virus (HCV) enters into human hepatocytes via tetraspanin hCD81. HCV glycoprotein E2 recognizes the "head" subdomain of the large extracellular loop (LEL) of CD81 (hCD81LEL), but the precise mechanism of virus cell attachment and entry remains elusive. Here, by combining the structural analysis of a conspicuous number of crystallized CD81LEL molecules with molecular dynamics simulations, we show that the conformational plasticity of the hCD81LEL head subdomain is a molecular property of the receptor...
November 21, 2016: Structure
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