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Protein Crystal Structure

Alain Dautant, Julien Henri, Thomas E Wales, Philippe Meyer, John R Engen, Florian Georgescauld
In order to be fully active and participate in the metabolism of phosphorylated nucleotides, most nucleoside diphosphate kinases (NDPK) have to assemble into stable hexamers. Here we studied the role played by six inter-subunit salt bridges R80-D93 in the stability of NDPK from the pathogen Mycobacterium tuberculosis ( Mt). Mutating R80 into Ala or Asn abolished the salt bridges. Unexpectedly, compensatory stabilizing mechanisms appeared for R80A and R80N mutants and we studied them by biochemical and structural methods...
February 20, 2019: Biochemistry
Jian-Ting Han, Si-Ping Zhang, Wen-Juan Jia, Zhang Zhang, Yong Wang, Yong-Xing He
The family of PhlG proteins catalyze the hydrolysis of carbon-carbon bonds and are widely distributed across diverse bacterial species. Two members of the PhlG family have been separately identified as 2,4-diacetylphloroglucinol hydrolase and phloretin hydrolase; however, the extent of functional divergence and catalytic substrates for most members of this family is still unknown. Here, using sequence similarity network and gene co-occurrence analysis, we categorized PhlG proteins into several subgroups and inferred that PhlG proteins from Mycobacterium abscessus (MaPhlG) are likely to be functionally equivalent to phloretin hydrolase...
February 19, 2019: FEBS Journal
Xiankun Cheng, Yanxiang Zhao, Qingshan Jiang, Jun Yang, Wensheng Zhao, Ian A Taylor, You-Liang Peng, Dongli Wang, Junfeng Liu
In rice, the critical regulator of the salicylic acid signalling pathway is OsWRKY45, a transcription factor (TF) of the WRKY TF family that functions by binding to the W-box of gene promoters, but the structural basis of OsWRKY45/W-box DNA recognition is unknown. Here, we show the crystal structure of the DNA binding domain of OsWRKY45 (OsWRKY45-DBD, i.e. the WRKY and zinc finger domain) in complex with a W-box DNA. Surprisingly, two OsWRKY45-DBD molecules exchange β4-β5 strands to form a dimer. The domain swapping occurs at the hinge region between the β3 and β4 strands, and is bridged and stabilized by zinc ion via coordinating residues from different chains...
February 20, 2019: Nucleic Acids Research
Xingyi Ma, Sojin Song, Soohyun Kim, Mi-Sun Kwon, Hyunsook Lee, Wounjhang Park, Sang Jun Sim
Consensus ranking of protein affinity to identify point mutations has not been established. Therefore, analytical techniques that can detect subtle variations without interfering with native biomolecular interactions are required. Here we report a rapid method to identify point mutations by a single nanoparticle sensing system. DNA-directed gold crystallization forms rod-like nanoparticles with bridges based on structural design. The nanoparticles enhance Rayleigh light scattering, achieving high refractive-index sensitivity, and enable the system to monitor even a small number of protein-DNA binding events without interference...
February 19, 2019: Nature Communications
Sumit J Bandekar, Nadia Arang, Ena S Tully, Brittany A Tang, Brenna L Barton, Sheng Li, J Silvio Gutkind, John J G Tesmer
The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gαq/11 subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gαq/11 -coupled G protein-coupled receptors (GPCRs) to control downstream events, such as cell motility and gene transcription. This conserved signal transduction axis is crucial for tumor growth in uveal melanoma. Previous studies indicate that the GEF activity of the TrioC module is autoinhibited, with release of autoinhibition upon Gαq/11 binding...
February 19, 2019: Science Signaling
Gautam Gunjan, Mohammad Sabir Ali, Alok Bhattacharya, Samudrala Gourinath
Motility and phagocytosis are key processes that are involved in invasive amoebiasis disease caused by intestinal parasite Entamoeba histolytica. Previous studies have reported unconventional myosins to play significant role in membrane based motility as well as endocytic processes. EhMyosin IB is the only unconventional myosin present in E. histolytica, is thought to be involved in both of these processes. Here, we report an interaction between the SH3 domain of EhMyosin IB and c-terminal domain of EhFP10, a Rho guanine nucleotide exchange factor...
February 19, 2019: PLoS Pathogens
Aljona Sitsel, Joren De Raeymaecker, Nikolaj Düring Drachmann, Rita Derua, Susanne Smaardijk, Jacob Lauwring Andersen, Ilse Vandecaetsbeek, Jialin Chen, Marc De Maeyer, Etienne Waelkens, Claus Olesen, Peter Vangheluwe, Poul Nissen
The sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase 2a (SERCA2a) performs active reuptake of cytoplasmic Ca2+ and is a major regulator of cardiac muscle contractility. Dysfunction or dysregulation of SERCA2a is associated with heart failure, while restoring its function is considered as a therapeutic strategy to restore cardiac performance. However, its structure has not yet been determined. Based on native, active protein purified from pig ventricular muscle, we present the first crystal structures of SERCA2a, determined in the CPA-stabilized E2-AlF4- form (3...
February 18, 2019: EMBO Journal
Mark A Bayfield, Jyotsna Vinayak, Kyra Kerkhofs, Farnaz Mansouri-Noori
La shuttles between the nucleus and cytoplasm where it binds nascent RNA polymerase III (pol III) transcripts and mRNAs, respectively. La protects the 3' end of pol III transcribed RNA precursors, such as pre-tRNAs, through the use of a well-characterized UUU-3'OH binding mode. La proteins are also RNA chaperones, and La-dependent RNA chaperone activity is hypothesized to promote pre-tRNA maturation and translation at cellular and viral internal ribosome entry sites via binding sites distinct from those used for UUU-3'OH recognition...
February 19, 2019: RNA Biology
Cécile Breyton, Waqas Javed, Annelise Vermot, Charles-Adrien Arnaud, Christine Hajjar, Jérôme Dupuy, Isabelle Petit-Hartlein, Aline Le Roy, Anne Martel, Michel Thépaut, Cédric Orelle, Jean-Michel Jault, Franck Fieschi, Lionel Porcar, Christine Ebel
Laurylmaltose neopentylglycol (LMNG) bears two linked hydrophobic chains of equal length and two hydrophilic maltoside groups. It arouses a strong interest in the field of membrane protein biochemistry, since it was shown to efficiently solubilize and stabilize membrane proteins often better than the commonly used dodecylmaltopyranoside (DDM), and to allow structure determination of some challenging membrane proteins. However, LMNG was described to form large micelles, which could be unfavorable for structural purposes...
February 15, 2019: Biochimica et biophysica acta. Biomembranes
Tien Khanh Nguyen, Hashiru Negishi, Satoshi Abe, Takafumi Ueno
Investigations involving the design of protein assemblies for the development of biomaterials are receiving significant attention. In nature, proteins can be driven into assemblies frequently by various non-covalent interactions. Assembly of proteins into supramolecules can be conducted under limited conditions in solution. These factors force the assembly process into an equilibrium state with low stability. Here, we report a new method for preparing assemblies using protein crystals as non-equilibrium molecular scaffolds...
January 28, 2019: Chemical Science
Ken Yong, Daniel Yuen, Moore Zhe Chen, Christopher J H Porter, Angus P R Johnston
Protein-conjugated nanoparticles have the potential to precisely deliver therapeutics to target sites in the body by specifically binding to cell surface receptors. To maximize targeting efficiency, the three-dimensional presentation of ligands towards these receptors is crucial. Herein, we demonstrate significantly enhanced targeting of nanoparticles to cancer cells by controlling the protein orientation on the nanoparticle surface. To engineer the point of attachment, we used amber codon reassignment to incorporate a synthetic amino acid, p-azidophenylalanine (azPhe), at specific locations within a single domain antibody (sdAb or nanobody) that recognizes the human epidermal growth factor receptor (EGFR)...
February 18, 2019: Nano Letters
Stuart Francis, Daniel Croft, Alexander W Schüttelkopf, Charles Parry, Angelo Pugliese, Ken Cameron, Sophie Claydon, Martin Drysdale, Claire Gardner, Andrea Gohlke, Gillian Goodwin, Christopher H Gray, Jennifer Konczal, Laura McDonald, Mokdad Mezna, Andrew Pannifer, Nikki R Paul, Laura Machesky, Heather McKinnon, Justin Bower
Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Structure-based elaboration of these compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin...
January 30, 2019: Bioorganic & Medicinal Chemistry Letters
Yasunori Watanabe, Seiya Watanabe, Yoshika Itoh, Yasuo Watanabe
The hypothetical OCC_00372 protein from Thermococcus litoralis is a member of the ProR superfamily from hyperthermophilic archaea and exhibits unique bifunctional proline racemase/hydroxyproline 2-epimerase activity. However, the molecular mechanism of the broad substrate specificity and extreme thermostability of this enzyme (TlProR) remains unclear. Here we determined the crystal structure of TlProR at 2.7 Å resolution. Of note, a substrate proline molecule, derived from expression host Escherichia coli cells, was tightly bound in the active site of TlProR...
February 14, 2019: Biochemical and Biophysical Research Communications
Yingsong Hu, Xiaodong Jia, Zhongyi Lu, Li Han
Aspergillus fumigatus is a major pathogen of invasive pulmonary aspergillosis with high mortality rate. The nucleoside diphosphate kinase of A. fumigatus, AfNDK (also called SwoH) is essential for its viability, however, its structural characteristic was unknown. In this study, we solved the crystal structure of AfNDK and found that it exists predominantly in form of tetramer in solution. Oligomeric form rather than dimeric form was essential for its kinase activity. The Arg30 and the C terminal amino acids were crucial for dimer-dimer interaction and the viability of A...
February 14, 2019: Biochemical and Biophysical Research Communications
Tamo Fukamizo, Yoshihito Kitaoku, Wipa Suginta
Periplasmic solute-binding proteins (SBPs) serve as molecular shuttles that assist the transport of small solutes from the outer membrane to the inner membrane of all Gram-negative bacteria. Based on the available crystal structures, SBPs are classified into seven clusters, A-G, and are further divided into subclusters, IV. This minireview is focused on the classification, structure and substrate specificity of a distinct class of SBPs specific for chitooligosaccharides (CBPs). To date, only two structures of CBP homologues, VhCBP and VcCBP, have been reported in the marine Vibrio species, with exposition of their limited function...
February 13, 2019: International Journal of Biological Macromolecules
M Teresa Bertran, Stéphane Mouilleron, Yanxiang Zhou, Rakhi Bajaj, Federico Uliana, Ganesan Senthil Kumar, Audrey van Drogen, Rebecca Lee, Jennifer J Banerjee, Simon Hauri, Nicola O'Reilly, Matthias Gstaiger, Rebecca Page, Wolfgang Peti, Nicolas Tapon
Serine/threonine phosphatases such as PP1 lack substrate specificity and associate with a large array of targeting subunits to achieve the requisite selectivity. The tumour suppressor ASPP (apoptosis-stimulating protein of p53) proteins associate with PP1 catalytic subunits and are implicated in multiple functions from transcriptional regulation to cell junction remodelling. Here we show that Drosophila ASPP is part of a multiprotein PP1 complex and that PP1 association is necessary for several in vivo functions of Drosophila ASPP...
February 15, 2019: Nature Communications
Kota Katayama, Sahil Gulati, Joseph T Ortega, Nathan S Alexander, Wenyu Sun, Marina M Shenouda, Krzysztof Palczewski, Beata Jastrzebska
The variable composition of the chromophore-binding pocket in visual receptors is essential for vision. The visual phototransduction starts with the cis-trans isomerization of the retinal chromophore upon absorption of photons. Despite sharing the common 11-cis-retinal chromophore, rod and cone photoreceptors possess distinct photochemical properties. Thus, a detailed molecular characterization of the chromophore-binding pocket of these receptors is critical to understanding the differences in the photochemistry of vision between rods and cones...
February 15, 2019: Journal of Biological Chemistry
Ming Peng, Xiu-Lan Chen, Dian Zhang, Xiu-Juan Wang, Ning Wang, Peng Wang, Jonathan D Todd, Yu-Zhong Zhang, Chun-Yang Li
The osmolyte dimethylsulfoniopropionate (DMSP) is produced in petagram quantities in marine environments and has important roles in global sulfur and carbon cycling. Many marine microorganisms catabolize DMSP via DMSP lyases generating the climate-active gas dimethyl sulfide (DMS). DMS oxidation products participate in forming cloud condensation nuclei, and thus may influence weather and climate. SAR11 bacteria are the most abundant marine heterotrophic bacteria, many of which contain the DMSP lyase DddK and whose dddK transcripts are relatively abundant in seawater...
February 15, 2019: Applied and Environmental Microbiology
Anandakrishnan Venkatesan, Jin-Yuan Fan, Samuel Bouyain, Jeffrey L Price
Drosophila Double-time (DBT) phosphorylates the circadian protein Period (PER). The period-altering mutation tau , identified in hamster casein kinase I (CKIε) and created in Drosophila DBT, has been shown to shorten the circadian period in flies, as it does in hamsters. Since CKI often phosphorylates downstream of previously phosphorylated residues and the tau amino acid binds a negatively charged ion in X-ray crystal structures, this amino acid has been suggested to contribute to a phosphate recognition site for the substrate...
February 14, 2019: International Journal of Molecular Sciences
Jingwei Weng, Wenning Wang
TolC is a channel protein responsible for substrate translocation across outer membrane, and it is also a part of the tripartite multidrug efflux pumps in Gram-negative bacteria. The crystal structure of TolC shows that the periplasmic entrance is tightly closed in the resting state, while substrate translocation definitely requires the entrance to open. How the occluded periplasmic entrance opens to allow passage of substrates remains elusive. In this work, we constructed a Markov state model from swarms of all-atom molecular dynamics (MD) simulation trajectories, which delineates the energetics of the conformational changes of TolC...
February 15, 2019: Journal of Chemical Information and Modeling
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