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Protein Crystal Structure

Jing Quan, Fawei Shen, Hao Cai, Yina Zhang, Hua Wu
Glycopolymers with large galactose units are attractive in biological processes because of their ability to selectively recognize lectin proteins. Recently, thermoresponsive double-hydrophilic block glycopolymers (TDHBGs) have been designed, which allow sugar residues to expose or hide via the lower critical solution temperature (LCST)-type phase transition. In this work, we first synthesize a new type of TDHBGs, composed of a thermoresponsive poly-di(ethylene glycol) methyl ether methacrylate block and a galactose-functionalized, poly-6-O-vinyladipoyl-D-galactose (POVNG) block...
August 16, 2018: Langmuir: the ACS Journal of Surfaces and Colloids
Bradley A Spicer, Ruby H P Law, Tom T Caradoc-Davies, Sue M Ekkel, Charles Bayly-Jones, Siew-Siew Pang, Paul J Conroy, Georg Ramm, Mazdak Radjainia, Hariprasad Venugopal, James C Whisstock, Michelle A Dunstone
Complement component 9 (C9) functions as the pore-forming component of the Membrane Attack Complex (MAC). During MAC assembly, multiple copies of C9 are sequentially recruited to membrane associated C5b8 to form a pore. Here we determined the 2.2 Å crystal structure of monomeric murine C9 and the 3.9 Å resolution cryo EM structure of C9 in a polymeric assembly. Comparison with other MAC proteins reveals that the first transmembrane region (TMH1) in monomeric C9 is uniquely positioned and functions to inhibit its self-assembly in the absence of C5b8...
August 15, 2018: Nature Communications
Ping Zhou, Yang She, Na Dong, Peng Li, Huabin He, Alessio Borio, Qingcui Wu, Shan Lu, Xiaojun Ding, Yong Cao, Yue Xu, Wenqing Gao, Mengqiu Dong, Jingjin Ding, Da-Cheng Wang, Alla Zamyatina, Feng Shao
Immune recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors often activates proinflammatory NF-κB signalling1 . Recent studies indicate that the bacterial metabolite D-glycero-β-D-manno-heptose 1,7-bisphosphate (HBP) can activate NF-κB signalling in host cytosol2-4 , but it is unclear whether HBP is a genuine PAMP and the cognate pattern recognition receptor has not been identified. Here we combined a transposon screen in Yersinia pseudotuberculosis with biochemical analyses and identified ADP-β-D-manno-heptose (ADP-Hep), which mediates type III secretion system-dependent NF-κB activation and cytokine expression...
August 15, 2018: Nature
Sergey A Buth, Mikhail M Shneider, Dean Scholl, Petr G Leiman
The R-type pyocins are high-molecular weight bacteriocins produced by some strains of Pseudomonas aeruginosa to specifically kill other strains of the same species. Structurally, the R-type pyocins are similar to "simple" contractile tails, such as those of phage P2 and Mu. The pyocin recognizes and binds to its target with the help of fibers that emanate from the baseplate structure at one end of the particle. Subsequently, the pyocin contracts its sheath and drives the rigid tube through the host cell envelope...
August 14, 2018: Viruses
Nitzan Kutnowski, Hagay Shmuely, Idit Dahan, Fania Shmulevich, Geula Davidov, Anat Shahar, Jerry Eichler, Raz Zarivach, Boaz Shaanan
Protein-DNA interactions are highly dependent on salt concentration. To gain insight into how such interactions are maintained in the highly saline cytoplasm of halophilic archaea, we determined the 3-D structure of VNG0258H/RosR, the first haloarchaeal DNA-binding protein from the extreme halophilic archaeon Halobactrium salinarum. It is a dimeric winged-helix-turn-helix (wHTH) protein with unique features due to adaptation to the halophilic environment. As ions are major players in DNA binding processes, particularly in the halophilic environments, we investigated the solution structure of the ionic envelope and located anions in the first shell around the protein in the crystal using anomalous scattering...
August 12, 2018: Journal of Structural Biology
Thembaninkosi G Gaule, Mark Andrew Smith, Katarzyna M Tych, Pascale Pirrat, Chi H Trinh, Arwen R Pearson, Peter F Knowles, Michael John McPherson
Copper amine oxidases (CuAOs) are metalloenzymes that reduce molecular oxygen to hydrogen peroxide during catalytic turnover of primary amines. In addition to Cu2+ in the active site, two peripheral calcium sites, ca. 32 Å from the active site, have roles in Escherichia coli amine oxidase (ECAO). The buried Ca2+ (Asp533, Leu534, Asp535, Asp678, Ala 679) is essential for full-length protein production, while the surface Ca2+ (Glu573, Tyr667, Asp670, Glu672) modulates biogenesis of the 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor...
August 15, 2018: Biochemistry
Martin Rennie, Gavin Fox, Javier Pérez, Peter B Crowley
Controlled protein assembly provides a means to regulate function. Supramolecular building blocks, including rigid macrocycles, have proven to be versatile triggers of protein assembly. Here, we show that sulfonato-calix[8]arene (sclx8) mediates the formation of cytochrome c tetramers in solution. This tetramer spontaneously disassembles at ≥ 2 equivalents of sclx8 providing a remarkable example of "auto-regulation". Using X-ray crystallography we characterize in detail the sclx8 binding sites on cytochrome c...
August 15, 2018: Angewandte Chemie
Manjeet Mukherjee, Sarah Sabir, Laura O'Regan, Josephina Sampson, Mark W Richards, Nicolas Huguenin-Dezot, James R Ault, Jason W Chin, Anastasia Zhuravleva, Andrew M Fry, Richard Bayliss
Hsp72 is a member of the 70-kDa heat shock family of molecular chaperones (Hsp70s) that comprise a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD) connected by a linker that couples the exchange of adenosine diphosphate (ADP) for adenosine triphosphate (ATP) with the release of the protein substrate. Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation...
August 14, 2018: Science Signaling
Hemant Kumar, Janet S Finer-Moore, Xiaoxu Jiang, Irina Smirnova, Vladimir Kasho, Els Pardon, Jan Steyaert, H Ronald Kaback, Robert M Stroud
The lactose permease of Escherichia coli (LacY), a dynamic polytopic membrane transport protein, catalyzes galactoside/H+ symport and operates by an alternating access mechanism that exhibits multiple conformations, the distribution of which is altered by sugar-binding. Camelid nanobodies were made against a double-mutant Gly46 → Trp/Gly262 → Trp (LacYWW ) that produces an outward-open conformation, as opposed to the cytoplasmic open-state crystal structure of WT LacY. Nanobody 9047 (Nb9047) stabilizes WT LacY in a periplasmic-open conformation...
August 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Min Zhu, Xiuchang Ma, Yongxiang Gao, Xiaowu Li, Jiyuan Ke, Muhammad Hidayatullah Khan, Maikun Teng, Honghua Ge, Zhongliang Zhu, Liwen Niu
By bearing a papain-like core structure and a cysteine-based catalytic triad, deamidase can convert glutamine to glutamic acid or asparagine to aspartic acid to modify the functions of host target proteins resulting in the blocking of eukaryotic host cell function. Legionella pneumophila effector Lpg2148 (MvcA) is a deamidase, a structural homolog of cycle inhibiting factor (Cif) effectors. Lpg2148 and Cif effectors are functionally diverse, with Lpg2148 only catalyzing ubiquitin but not NEDD8. However, a detailed understanding of substrate specificity is still missing...
August 11, 2018: Biochemical and Biophysical Research Communications
Fei Shang, Jinli Chen, Lulu Wang, Liming Jin, Linhai Zou, Tingting Bu, Yuesheng Dong, Nam-Chul Ha, Ki Hyun Nam, Chunshan Quan, Yongbin Xu
The nicotinamidase/pyrazinamidase PncA is a member of a large family of hydrolase enzymes that catalyze the deamination of nicotinamide to nicotinic acid. PncA also functions as a pyrazinamidase in a wide variety of eubacteria and is an essential coenzyme in many cellular redox reactions in living systems. We report the crystal structure of substrate-free PncA from Bacillus subtilis (BsPncA) at 2.0 Å resolution to improve our understanding of the PncA family. The structure of BsPncA consists of an α/β domain and a subdomain...
August 11, 2018: Biochemical and Biophysical Research Communications
Jesper S Johansen, Darius Kavaliauskas, Shawn H Pfeil, Mickaël Blaise, Barry S Cooperman, Yale E Goldman, Søren S Thirup, Charlotte R Knudsen
According to the traditional view, GTPases act as molecular switches, which cycle between distinct 'on' and 'off' conformations bound to GTP and GDP, respectively. Translation elongation factor EF-Tu is a GTPase essential for prokaryotic protein synthesis. In its GTP-bound form, EF-Tu delivers aminoacylated tRNAs to the ribosome as a ternary complex. GTP hydrolysis is thought to cause the release of EF-Tu from aminoacyl-tRNA and the ribosome due to a dramatic conformational change following Pi release. Here, the crystal structure of Escherichia coli EF-Tu in complex with a non-hydrolysable GTP analogue (GDPNP) has been determined...
August 11, 2018: Nucleic Acids Research
Eric A Wold, Jianping Chen, Kathryn A Cunningham, Jia Zhou
G protein-coupled receptors (GPCRs) have been tractable drug targets for decades with over one-third of currently marketed drugs targeting GPCRs. Of these, the class A GPCR superfamily is highly represented and continued drug discovery for this family of receptors may provide novel therapeutics for a vast range of diseases. GPCR allosteric modulation is an innovative targeting approach that broadens the available small molecule toolbox and is proving to be a viable drug discovery strategy, as evidenced by recent FDA approvals and clinical trials...
August 14, 2018: Journal of Medicinal Chemistry
Federico Mantoni, Alessandro Paiardini, Paolo Brunotti, Cecilia D'Angelo, Laura Cervoni, Alessio Paone, Loredana Cappellacci, Riccardo Petrelli, Massimo Ricciutelli, Livia Leoni, Giordano Rampioni, Alessandro Arcovito, Serena Rinaldo, Francesca Cutruzzolà, Giorgio Giardina
Bis-(3'-5')-cyclic diguanylic acid (c-di-GMP) belongs to the class of cyclic dinucleotides, key carriers of cellular information in prokaryotic and eukaryotic signal transduction pathways. In bacteria, the intracellular levels of c-di-GMP and their complex physiological outputs are dynamically regulated by environmental and internal stimuli, which control the antagonistic activities of diguanylate cyclases (DGCs) and c-di-GMP specific phosphodiesterases (PDEs). Allostery is one of the major modulators of the c-di-GMP-dependent response...
August 14, 2018: FEBS Journal
Yujiro Higuchi, Hitomi Matsufuji, Masanari Tanuma, Takatoshi Arakawa, Kazuki Mori, Chihaya Yamada, Risa Shofia, Emiko Matsunaga, Kosuke Tashiro, Shinya Fushinobu, Kaoru Takegawa
Pyruvyl modification of oligosaccharides is widely seen in both prokaryotes and eukaryotes. Although the biosynthetic mechanisms of pyruvylation have been investigated, enzymes that metabolize and degrade pyruvylated oligosaccharides are not well known. Here, we searched for a pyruvylated galactose (PvGal)-releasing enzyme by screening soil samples. We identified a Bacillus strain, as confirmed by the 16S ribosomal RNA gene analysis, that exhibited PvGal-ase activity toward p-nitrophenyl-β-D-pyruvylated galactopyranose (pNP-β-D-PvGal)...
August 13, 2018: Scientific Reports
Manickam Yogavel, Joanne E Nettleship, Akansha Sharma, Karl Harlos, Abhishek Jamwal, Rini Chaturvedi, Manmohan Sharma, Vitul Jain, Jyoti Chhibber-Goel, Amit Sharma
The genomes of the malaria-causing Plasmodium parasites encode a protein fused of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS) domains that catalyze sequential reactions in the folate biosynthetic pathway. Whereas higher organisms derive folate from their diet and lack the enzymes for its synthesis, most eubacteria and a number of lower eukaryotes including malaria parasites synthesize tetrahydrofolate via DHPS. Plasmodium falciparum ( Pf ) and Plasmodium vivax ( Pv ) HPPK-DHPSs are currently targets of drugs like sulfadoxine (SDX)...
August 13, 2018: Journal of Biological Chemistry
Sharifah Nur Hidayah Syed Mazlan, Mohd Shukuri Mohamad Ali, Raja Noor Zaliha Raja Abd Rahman, Suriana Sabri, Mohd Anuar Jonet, Leow Thean Chor
GDSL esterase J15 (EstJ15) is a member of Family II of lipolytic enzyme. The enzyme was further classified in subgroup SGNH hydrolase due to the presence of highly conserve motif, Ser-Gly-Asn-His in four conserved blocks I, II, III, and V, respectively. X-ray quality crystal of EstJ15 was obtained from optimized formulation containing 0.10 M ammonium sulphate, 0.15 M sodium cacodylate trihydrate pH 6.5, and 20% PEG 8000. The crystal structure of EstJ15 was solved at 1.38 Å with one molecule per asymmetric unit...
August 10, 2018: International Journal of Biological Macromolecules
Juliette Fedry, Jennifer Forcina, Pierre Legrand, Gérard Péhau-Arnaudet, Ahmed Haouz, Mark Johnson, Felix A Rey, Thomas Krey
HAPLESS2 (HAP2) is a broadly conserved, gamete-expressed transmembrane protein that was shown recently to be structurally homologous to viral class II fusion proteins, which initiate fusion with host cells via insertion of fusion loops into the host membrane. However, the functional conformation of the HAP2 fusion loops has remained unknown, as the reported X-ray structure of Chlamydomonas reinhardtii HAP2 lacked this critical region. Here, we report a structure-guided alignment that reveals diversification of the proposed HAP2 fusion loops...
August 2018: PLoS Biology
Roy Nassar, Eric Wong, Jennifer M Bui, Calvin Yip, Hongbin Li, Joerg A Gsponer, Guillaume Lamour
Mapping the nanomechanical properties of amyloids can provide valuable insights into structure and assembly mechanisms of protein aggregates that underlie the development of various human diseases. Although it is well known that amyloids exhibit an intrinsic stiffness comparable to that of silk (1-10 GPa), a detailed understanding of the directional dependence (anisotropy) of the stiffness of amyloids and how it relates to structural features in these protein aggregates is missing. Here we used steered molecular dynamics (SMD) simulations and amplitude modulation-frequency modulation (AM-FM) atomic force microscopy to measure the directional variation in stiffness of GNNQQNY amyloid crystals...
August 13, 2018: Journal of Physical Chemistry Letters
Michael P Bokoch, Hyunil Jo, James R Valcourt, Yoga Srinivasan, Albert C Pan, Sara Capponi, Michael Grabe, Ron O Dror, David E Shaw, William F DeGrado, Shaun R Coughlin
The pathways that G protein-coupled receptor (GPCR) ligands follow as they bind to or dissociate from their receptors are largely unknown. Protease-activated receptor 1 (PAR1) is a GPCR activated by intramolecular binding of a tethered agonist peptide that is exposed by thrombin cleavage. By contrast, the PAR1 antagonist vorapaxar is a lipophilic drug that binds in a pocket almost entirely occluded from extracellular solvent. The binding and dissociation pathway of vorapaxar is unknown. Starting with the crystal structure of vorapaxar bound to PAR1, we performed temperature-accelerated molecular dynamics simulations of ligand dissociation...
August 13, 2018: Biochemistry
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