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https://www.readbyqxmd.com/read/29775455/atomic-resolution-mechanism-of-ligand-binding-to-a-solvent-inaccessible-cavity-in-t4-lysozyme
#1
Jagannath Mondal, Navjeet Ahalawat, Subhendu Pandit, Lewis E Kay, Pramodh Vallurupalli
Ligand binding sites in proteins are often localized to deeply buried cavities, inaccessible to bulk solvent. Yet, in many cases binding of cognate ligands occurs rapidly. An intriguing system is presented by the L99A cavity mutant of T4 Lysozyme (T4L L99A) that rapidly binds benzene (~106 M-1s-1). Although the protein has long served as a model system for protein thermodynamics and crystal structures of both free and benzene-bound T4L L99A are available, the kinetic pathways by which benzene reaches its solvent-inaccessible binding cavity remain elusive...
May 18, 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29775417/targeting-histone-methyltransferase-enhancer-of-zeste-homolog-2-inhibits-renal-epithelial-mesenchymal-transition-and-attenuates-renal-fibrosis
#2
Xiaoxu Zhou, Chongxiang Xiong, Evelyn Tolbert, Ting C Zhao, George Bayliss, Shougang Zhuang
Enhancer of zeste homolog-2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. Its role in renal epithelial-mesenchymal transition (EMT) remains unknown. In this study, we found that EZH2 and H3K27me3 were highly expressed in mouse kidney with unilateral ureteral obstruction and cultured mouse kidney proximal tubular (TKPT) cells undergoing EMT. Inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) attenuated renal fibrosis, which was associated with preserving E-cadherin expression and inhibiting Vimentin up-regulation in the obstructed kidney...
May 18, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29775310/fragment-based-discovery-of-a-potent-orally-bioavailable-inhibitor-which-modulates-the-phosphorylation-and-catalytic-activity-of-erk1-2
#3
Tom D Heightman, Valerio Berdini, Hannah Braithwaite, Ildiko Maria Buck, Megan Cassidy, Juan Castro, Aurelie Courtin, James E H Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M Griffiths-Jones, John F Lyons, Vanessa Martins, Sandra Muench, Joanne M Munck, David Norton, Marc O'Reilly, Nick Palmer, Puja Pathuri, Michael Reader, David C Rees, Sharna J Rich, Caroline Richardson, Harpreet Saini, Neil T Thompson, Nicola G Wallis, Hugh Walton, Nicola E Wilsher, Alison J-A Woolford, Michael Cooke, David Cousin, Stuart Onions, Jonathan Shannon, John Watts, Christopher W Murray
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775281/highly-stretchable-waterproof-fiber-asymmetric-supercapacitors-in-an-integrated-structure
#4
Kai Guo, Xianfu Wang, Lintong Hu, Tianyou Zhai, Huiqiao Li, Neng Yu
Fiber supercapacitors have attracted tremendous attention as promising power source candidates for next generation of wearable electronics, which are flexible, stretchable, and washable. Although asymmetric fiber supercapacitors with a high energy density have been achieved, their stretchability is no more than 200%, and they still face mechanical instability and unreliable waterproof structure. This work develops a highly integrated structure for waterproof, highly stretchable and asymmetric fiber-shaped supercapacitor, which is assembled by integrating a helix-shaped asymmetric fiber supercapacitor into a bifunctional polymer...
May 18, 2018: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29774746/nonlinear-optical-behaviors-of-a-chiral-metal-organic-framework-comprised-of-an-unusual-multioriented-double-helix-structure
#5
Xiaoli Huang, Qiyang Li, Xue Xiao, Shuping Jia, Yue Li, Zhigang Duan, Lei Bai, Ze Yuan, Lin Li, Zhihua Lin, Yonggang Zhao
We present here the synthesis of one enantiomeric pair of metal-organic framework materials comprised of a unique multioriented double-helix structure from an achiral spirocenter ligand. Our study clearly shows that the chiral MOF material encompasses concurrently multiple nonlinear-optical functions in the solid state: the noncentrosymmetric structural feature brings the chiral MOF high second-harmonic-generation efficiency; the incorporation of the spirocenter ligand can efficiently produce two-photon-excited photoluminescence with a larger-action cross-sectional value...
May 18, 2018: Inorganic Chemistry
https://www.readbyqxmd.com/read/29773713/a-thumbwheel-mechanism-for-apoa1-activation-of-lcat-activity-in-hdl
#6
Allison L Cooke, Jamie Morris, John T Melchior, Scott E Street, W Gray Jerome, Rong Huang, Andrew B Herr, Loren E Smith, Jere P Segrest, Alan T Remaley, Amy S Shah, Thomas B Thompson, W Sean Davidson
APOA1 is the most abundant protein in HDL. It modulates interactions that affect HDLs cardioprotective functions, in part via its activation of the enzyme LCAT. On nascent, discoidal HDL, APOA1 comprises 10 alpha-helical repeats arranged in an anti-parallel, stacked-ring structure that encapsulates a lipid bilayer. Previous chemical cross-linking studies suggested that these APOA1 rings can adopt at least two different orientations, or registries, with respect to each other; however, the functional impact of these structural changes is unknown...
May 17, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29773644/bhlhe40-is-an-essential-repressor-of-il-10-during-mycobacterium-tuberculosis-infection
#7
Jeremy P Huynh, Chih-Chung Lin, Jacqueline M Kimmey, Nicholas N Jarjour, Elizabeth A Schwarzkopf, Tara R Bradstreet, Irina Shchukina, Oleg Shpynov, Casey T Weaver, Reshma Taneja, Maxim N Artyomov, Brian T Edelson, Christina L Stallings
The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis ( Mtb ) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ...
May 17, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29773051/dna-topoisomerases-of-leishmania-parasites-druggable-targets-for-drug-discovery
#8
Rosa Mª Reguer, Ehab Kotb Elmahallaw, Carlos Garcia-Estrada, Ruben Carbajo-Andres, Rafael Balana-Fouce
DNA topoisomerases (Top) are a group of isomerase enzymes responsible for controlling the topological problems caused by DNA double helix in the cell during the processes of replication, transcription and recombination. Interestingly, these enzymes have been known since long to be key molecular machines in several cellular processes through overwinding or underwinding of DNA in all-living organisms. Leishmania, a trypanosomatid parasite responsible for causing fatal diseases mostly in impoverished populations of low-income countries, have a set of six classes of Top enzymes...
May 17, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29771508/comparison-of-kinetics-toxicity-oligomers-formation-and-membrane-binding-capacity-of-%C3%AE-synuclein-familial-mutations-at-a53-site-including-newly-discovered-a53v-mutation
#9
Ganesh M Mohite, Rakesh Kumar, Rajlaxmi Panigrahi, Ambuja Navalkar, Nitu Singh, Debalina Datta, Surabhi Mehra, Soumik Ray, Laxmikant G Gadhe, Subhadeep Das, Namrata Singh, Debdeep Chatterjee, Ashutosh Kumar, Samir K Maji
The involvement of α-synuclein (α-Syn) amyloid formation in Parkinson's disease (PD) pathogenesis is supported by the discovery of α-Syn gene (SNCA) mutations linked with familial PD, which are known to modulate the oligomerization and aggregation of α-Syn. Recently, the A53V mutation has been discovered, which leads to the late-onset PD. In the present study, we characterized for the first time the biophysical properties including the aggregation propensities, toxicity of aggregated species and membrane binding capability of A53V along with all familial mutations at A53 position...
May 17, 2018: Biochemistry
https://www.readbyqxmd.com/read/29771498/structure-and-function-of-the-transmembrane-domain-of-nsas-an-antibiotic-sensing-histidine-kinase-in-s-aureus
#10
Manasi P Bhate, Thomas Lemmin, Georg Kuenze, Bruk Mensa, Soumya Ganguly, Jason Peters, Nathan Schmidt, Jeffrey G Pelton, Carol Gross, Jens Meiler, William F DeGrado
NsaS is one of four intramembrane histidine kinases (HKs) in Staphylococcus aureus that mediate the pathogen's response to membrane active antimicrobials and human innate immunity. We describe the first integrative structural study of NsaS using a combination of solution state NMR spectroscopy, chemical-crosslinking, molecular modeling and dynamics. Three key structural features emerge: First, NsaS has a short N-terminal amphiphilic helix that anchors its transmembrane (TM) bundle into the inner leaflet of the membrane such that it might sense neighboring proteins or membrane deformations...
May 17, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29770977/formation-of-twisted-%C3%AE-sheet-tapes-from-a-self-complementary-peptide-based-on-novel-pillararene-gcp-host-guest-interaction-with-gene-transfection-properties
#11
Carsten Schmuck, Xiao-Yu Hu, Martin Ehlers, Elio Zellermann, Stefanie Mosel, Hao Jiang, Jan-Erik Ostwaldt, Shirley Knauer, Leyong Wang, Tingting Wang
Small peptides capable of assembling into well-defined nanostructures have attracted extensive attention due to their interesting applications as biomaterials. Herein, we report the first example of a pillararene functionalized with a guanidiniocarbonyl pyrrole (GCP)-conjugated short peptide segment. The obtained amphiphilic peptide 1 spontaneously self-assembles into a supramolecular β-sheet in aqueous solution based on host-guest interaction between pillararene and GCP unit as well as hydrogen-bonding between the peptide strands...
May 17, 2018: Chemistry: a European Journal
https://www.readbyqxmd.com/read/29770645/atoh1-regulation-in-the-cochlea-more-than-just-transcription
#12
REVIEW
Yen-Fu Cheng
More than 80% of all cases of deafness are related to the death or degeneration of cochlear hair cells and the associated spiral ganglion neurons, and a lack of regeneration of these cells leads to permanent hearing loss. Therefore, the regeneration of lost hair cells is an important goal for the treatment of deafness. Atoh1 is a basic helix-loop-helix (bHLH) transcription factor that is critical in both the development and regeneration of cochlear hair cells. Atoh1 is transcriptionally regulated by several signaling pathways, including Notch and Wnt signalings...
July 13, 2017: Journal of Zhejiang University. Science. B
https://www.readbyqxmd.com/read/29770128/critical-functions-of-region-1-67-and-helix-xiii-in-retaining-the-active-structure-of-nhad-antiporter-in-halomonas-sp-y2
#13
Zhou Yang, Yiwei Meng, Qi Zhao, Bin Cheng, Ping Xu, Chunyu Yang
NhaD-type antiporters are mainly distributed in various Proteobacteria , especially in marine microorganisms and human pathogens. This distribution as well as the pathogenic properties of these strains suggest that these antiporters contribute to the regulation of high osmoregulation and are potential drug targets. Two NhaD homologs, NhaD1 and NhaD2, from the halotolerant and alkaliphilic Halomonas sp. Y2 exhibits similar, high in vitro activity, but remarkably different in vivo functions. To search for critical domains or residues involved in these differences of physiological functions, various chimeras composed of NhaD1 and NhaD2 segments were generated...
2018: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29769343/glycoprotein-3-of-porcine-reproductive-and-respiratory-syndrome-virus-exhibits-an-unusual-hairpin-like-membrane-topology
#14
Minze Zhang, Ludwig Krabben, Fangkun Wang, Michael Veit
The glycoprotein GP3 of the Arterivirus porcine reproductive and respiratory syndrome virus (PRRSV) consists of a cleaved signal peptide, a highly glycosylated domain, a short hydrophobic region and an unglycosylated C-terminal domain. GP3 is supposed to form a complex with GP2 and GP4 in virus particles, but secretion of GP3 from cells has also been reported.We analyzed the membrane topology of GP3 from various PRRSV strains. A fraction of the protein is secreted from transfected cells; GP3 from PRRSV-1 strains to a greater extent than GP3 from PRRSV-2 strains...
May 16, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29769318/structural-basis-for-selective-inhibition-of-human-pkg-i%C3%AE-by-the-balanol-like-compound-n46
#15
Liying Qin, Banumathi Sankaran, Sahar Aminzai, Darren Casteel, Choel Kim
Activation of PKG Iα in nociceptive neurons induces a long-term hyperexcitability that causes chronic pain. Recently, a derivative of the fungal metabolite balanol, N46, has been reported to inhibit PKG Iα with high potency and selectivity and attenuates thermal hyperalgesia and osteoarthritic pain. Here, we determined co-crystal structures of the PKG Iα C-domain and cAMP-dependent protein kinase (PKA) Cα, each bound with N46, at 1.98 Å and 2.65 Å, respectively. N46 binds the active site with its external phenyl ring specifically interacting with the glycine-rich loop and the αC helix...
May 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29768206/intrinsic-instability-of-bok-enables-membrane-permeabilization-in-apoptosis
#16
Janet H Zheng, Christy R Grace, Cristina D Guibao, Dan E McNamara, Fabien Llambi, Yue-Ming Wang, Taosheng Chen, Tudor Moldoveanu
The effector B cell lymphoma-2 (BCL-2) protein BCL-2 ovarian killer (BOK) induces mitochondrial outer membrane permeabilization (MOMP) to initiate apoptosis upon inhibition of the proteasome. How BOK mediates MOMP is mechanistically unknown. The NMR structure of the BCL-2 core of human BOK reveals a conserved architecture with an atypical hydrophobic groove that undergoes conformational exchange. Remarkably, the BCL-2 core of BOK spontaneously associates with purified mitochondria to release cytochrome c in MOMP assays...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29768204/an-amphipathic-helix-directs-cellular-membrane-curvature-sensing-and-function-of-the-bar-domain-protein-pick1
#17
Rasmus Herlo, Viktor K Lund, Matthew D Lycas, Anna M Jansen, George Khelashvili, Rita C Andersen, Vikram Bhatia, Thomas S Pedersen, Pedro B C Albornoz, Niklaus Johner, Ina Ammendrup-Johnsen, Nikolaj R Christensen, Simon Erlendsson, Mikkel Stoklund, Jannik B Larsen, Harel Weinstein, Ole Kjærulff, Dimitrios Stamou, Ulrik Gether, Kenneth L Madsen
BAR domains are dimeric protein modules that sense, induce, and stabilize lipid membrane curvature. Here, we show that membrane curvature sensing (MCS) directs cellular localization and function of the BAR domain protein PICK1. In PICK1, and the homologous proteins ICA69 and arfaptin2, we identify an amphipathic helix N-terminal to the BAR domain that mediates MCS. Mutational disruption of the helix in PICK1 impaired MCS without affecting membrane binding per se. In insulin-producing INS-1E cells, super-resolution microscopy revealed that disruption of the helix selectively compromised PICK1 density on insulin granules of high curvature during their maturation...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29767523/microscopic-insight-into-the-protein-denaturation-action-of-urea-and-its-methyl-derivatives
#18
Bei Ding, Lijiang Yang, Debopreeti Mukherjee, Jianxin Chen, Yi Qin Gao, Feng Gai
: We employ site-specific, linear and nonlinear infrared spectroscopic techniques as well as fluorescence spectroscopy and molecular dynamics simulations to investigate the binding interactions of urea and three of its derivatives, methylurea, 1,3-dimethylurea and tetramethylurea, with protein aromatic and polar sidechains. We find that (1) urea methylation leads to preferential interactions between the co-solvent molecules and aromatic sidechains with an affinity that increases with the number of methyl groups; (2) interactions with tetramethylurea cause significant dehydration of aromatic sidechains and the effect is most pronounced for tryptophan; and (3) while neither urea nor tetramethylurea shows preferential accumulation around a polar sidechain, the number of hydrogen-bond donors around this sidechain is significantly decreased in the presence of tetramethylurea...
May 16, 2018: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/29766792/gabaa-receptors-various-stoichiometrics-of-subunit-arrangement-in-%C3%AE-1%C3%AE-3-and-%C3%AE-1%C3%AE-3%C3%AE%C2%B5-receptors
#19
Ahmad Tarmizi Che Has, Mary Chebib
GABAA receptors (GABAARs) are members of the Cys-loop ligand-gated ion channel (LGIC) superfamily, which includes nicotinic acetylcholine, glycine, and serotonin (5HT3) receptors [1,2,3,4]. LGICs typically mediate fast synaptic transmission via the movement of ions through channels gated by neurotransmitters, such as acetylcholine for nicotinic receptors and GABA for GABAARs [5]. The term Cys-loop receptors originates from the presence of a conserved disulphide bond (or bridge) which holds together two cysteine amino acids of the loop that forms from the structure of polypeptides in the extracellular domain of the receptor's subunit [6]...
May 15, 2018: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29766661/structure-based-design-of-a-eukaryote-selective-antiprotozoal-fluorinated-aminoglycoside
#20
Hiroki Kanazawa, Oscar M Saavedra, Juan Pablo Maianti, Simon A Young, Luis Izquierdo, Terry K Smith, Stephen Hanessian, Jiro Kondo
Aminoglycosides (AG) are antibiotics that lower the accuracy of protein synthesis by targeting a highly-conserved RNA helix of the ribosomal A-site. The discovery of AGs that selectively target the eukaryotic ribosome, but lack activity in prokaryotes, are promising as antiprotozoals for the treatment of neglected tropical diseases, and as therapies to read-through point-mutation genetic diseases. However, a single nucleobase change A1408G in the eukaryotic A-site leads to negligible affinity for most AGs. Herein we report the synthesis of 6'-fluoro sisomicin, the first 6'-fluorinated aminoglycoside, which specifically interacts with the protozoal cytoplasmic rRNA A-site, but not the bacterial A-site, as evidenced by X-ray co-crystal structures...
May 15, 2018: ChemMedChem
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