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- Keyword
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- Models, Molecular (4)
- Molecular Structure (3)
- Neuroinflammation (3)
- Alzheimer’s disease (2)
- Amines (2)
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- Animals (2)
- Binding Sites (2)
- Crystallography, X-Ray (2)
- Glycosylation (2)
- Humans (2)
- Molecular Conformation (2)
- Neurodegeneration (2)
- Protein Binding (2)
- Protein Conformation (2)
- 14C (1)
- 26Al (1)
- ATP binding cassette transporter G5 (1)
- ATP binding cassette transporter G8 (1)
- ATPase (1)
- Accelerator mass spectrometry (1)
- Acute myeloid leukemia (1)
- Adenosine Triphosphatases (1)
- Adenosine Triphosphate (1)
- Aequorin (1)
- Aequorin variants (1)
- Aglianico del Vulture (1)
- Agronomic performance (1)
- Alcohol use disorder (1)
- Allosteric inhibitory site (1)
- Aluminum (1)
Articles 1 - 24 of 24
Full-Text Articles in Pharmacy and Pharmaceutical Sciences
Prostacyclin Promotes Degenerative Pathology In A Model Of Alzheimer’S Disease, Tasha R. Womack, Craig T. Vollert, Odochi Ohia-Nwoko, Monika Schmitt, Saghi Montazari, Tina L. Beckett, David Mayerich, M. Paul Murphy, Jason L. Eriksen
Prostacyclin Promotes Degenerative Pathology In A Model Of Alzheimer’S Disease, Tasha R. Womack, Craig T. Vollert, Odochi Ohia-Nwoko, Monika Schmitt, Saghi Montazari, Tina L. Beckett, David Mayerich, M. Paul Murphy, Jason L. Eriksen
Molecular and Cellular Biochemistry Faculty Publications
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the most common form of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression …
Phenolic Compounds Of Red Wine Aglianico Del Vulture Modulate The Functional Activity Of Macrophages Via Inhibition Of Nf-Κb And The Citrate Pathway, Anna Santarsiero, Paolo Convertini, Antonio Vassallo, Valentina Santoro, Simona Todisco, Dominga Iacobazzi, Yvonne N. Fondufe-Mittendorf, Giuseppe Martelli, Marcos R. De Oliveira, Rosangela Montanaro, Vincenzo Brancaleone, Johannes Stöckl, Vittoria Infantino
Phenolic Compounds Of Red Wine Aglianico Del Vulture Modulate The Functional Activity Of Macrophages Via Inhibition Of Nf-Κb And The Citrate Pathway, Anna Santarsiero, Paolo Convertini, Antonio Vassallo, Valentina Santoro, Simona Todisco, Dominga Iacobazzi, Yvonne N. Fondufe-Mittendorf, Giuseppe Martelli, Marcos R. De Oliveira, Rosangela Montanaro, Vincenzo Brancaleone, Johannes Stöckl, Vittoria Infantino
Molecular and Cellular Biochemistry Faculty Publications
Phenolic compounds of red wine powder (RWP) extracted from the Italian red wine Aglianico del Vulture have been investigated for the potential immunomodulatory and anti-inflammatory capacity on human macrophages. These compounds reduce the secretion of IL-1β, IL-6, and TNF-α proinflammatory cytokines and increase the release of IL-10 anti-inflammatory cytokine induced by lipopolysaccharide (LPS). In addition, RWP restores Annexin A1 levels, thus involving activation of proresolutive pathways. Noteworthy, RWP lowers NF-κB protein levels, promoter activity, and nuclear translocation. As a consequence of NF-κB inhibition, reduced promoter activities of SLC25A1—encoding the mitochondrial citrate carrier …
The Context-Dependent Impact Of Integrin-Associated Cd151 And Other Tetraspanins On Cancer Development And Progression: A Class Of Versatile Mediators Of Cellular Function And Signaling, Tumorigenesis And Metastasis, Sonia F. Erfani, Hui Hua, Yueyin Pan, Binhua P. Zhou, Xiuwei H. Yang
The Context-Dependent Impact Of Integrin-Associated Cd151 And Other Tetraspanins On Cancer Development And Progression: A Class Of Versatile Mediators Of Cellular Function And Signaling, Tumorigenesis And Metastasis, Sonia F. Erfani, Hui Hua, Yueyin Pan, Binhua P. Zhou, Xiuwei H. Yang
Molecular and Cellular Biochemistry Faculty Publications
As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition …
Chronic Voluntary Alcohol Drinking Causes Anxiety-Like Behavior, Thiamine Deficiency, And Brain Damage Of Female Crossed High Alcohol Preferring Mice, Hong Xu, Hui Li, Dexiang Liu, Wen Wen, Mei Xu, Jacqueline A. Frank, Jing Chen, Haining Zhu, Nicholas J. Grahame, Jia Luo
Chronic Voluntary Alcohol Drinking Causes Anxiety-Like Behavior, Thiamine Deficiency, And Brain Damage Of Female Crossed High Alcohol Preferring Mice, Hong Xu, Hui Li, Dexiang Liu, Wen Wen, Mei Xu, Jacqueline A. Frank, Jing Chen, Haining Zhu, Nicholas J. Grahame, Jia Luo
Molecular and Cellular Biochemistry Faculty Publications
The central nervous system is vulnerable to chronic alcohol abuse, and alcohol dependence is a chronically relapsing disorder which causes a variety of physical and mental disorders. Appropriate animal models are important for investigating the underlying cellular and molecular mechanisms. The crossed High Alcohol Preferring mice prefer alcohol to water when given free access. In the present study, we used female cHAP mice as a model of chronic voluntary drinking to evaluate the effects of alcohol on neurobehavioral and neuropathological changes. The female cHAP mice had free-choice access to 10% ethanol and water, while control mice had access to water …
Arginase 1 Insufficiency Precipitates Amyloid-Β Deposition And Hastens Behavioral Impairment In A Mouse Model Of Amyloidosis, Chao Ma, Jerry B. Hunt, Maj-Linda B. Selenica, Awa Sanneh, Leslie A. Sandusky-Beltran, Mallory Watler, Rana Daas, Andrii Kovalenko, Huimin Liang, Devon Placides, Chuanhai Cao, Xiaoyang Lin, Michael B. Orr, Bei Zhang, John C. Gensel, David J. Feola, Marcia N. Gordon, Dave Morgan, Paula C. Bickford, Daniel C. Lee
Arginase 1 Insufficiency Precipitates Amyloid-Β Deposition And Hastens Behavioral Impairment In A Mouse Model Of Amyloidosis, Chao Ma, Jerry B. Hunt, Maj-Linda B. Selenica, Awa Sanneh, Leslie A. Sandusky-Beltran, Mallory Watler, Rana Daas, Andrii Kovalenko, Huimin Liang, Devon Placides, Chuanhai Cao, Xiaoyang Lin, Michael B. Orr, Bei Zhang, John C. Gensel, David J. Feola, Marcia N. Gordon, Dave Morgan, Paula C. Bickford, Daniel C. Lee
Sanders-Brown Center on Aging Faculty Publications
Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1 …
Epigenetic Regulation Of Wnt Signaling By Carboxamide-Substituted Benzhydryl Amines That Function As Histone Demethylase Inhibitors, Wen Zhang, Vitaliy M. Sviripa, Yanqi Xie, Tianxin Yu, Meghan G. Haney, Jessica S. Blackburn, Charles A. Adeniran, Chang-Guo Zhan, David S. Watt, Chunming Liu
Epigenetic Regulation Of Wnt Signaling By Carboxamide-Substituted Benzhydryl Amines That Function As Histone Demethylase Inhibitors, Wen Zhang, Vitaliy M. Sviripa, Yanqi Xie, Tianxin Yu, Meghan G. Haney, Jessica S. Blackburn, Charles A. Adeniran, Chang-Guo Zhan, David S. Watt, Chunming Liu
Molecular and Cellular Biochemistry Faculty Publications
Aberrant activation of Wnt signaling triggered by mutations in either Adenomatous Polyposis Coli (APC) or CTNNB1 (β-catenin) is a hallmark of colorectal cancers (CRC). As part of a program to develop epigenetic regulators for cancer therapy, we developed carboxamide-substituted benzhydryl amines (CBAs) bearing either aryl or heteroaryl groups that selectively targeted histone lysine demethylases (KDMs) and functioned as inhibitors of the Wnt pathway. A biotinylated variant of N-((5-chloro-8-hydroxyquinolin-7-yl) (4-(diethylamino)phenyl)-methyl)butyramide (CBA-1) identified KDM3A as a binding partner. KDM3A is a Jumonji (JmjC) domain-containing demethylase that is significantly upregulated in CRC. KDM3A regulates the demethylation of histone H3's lysine …
Canvass: A Crowd-Sourced, Natural-Product Screening Library For Exploring Biological Space, Sara E. Kearney, Gergely ZahoráNszky-KőHalmi, Kyle R. Brimacombe, Mark J. Henderson, Caitlin Lynch, Tongan Zhao, Kanny K. Wan, Zina Itkin, Christopher Dillon, Min Shen, Dorian M. Cheff, Tobie D. Lee, Danielle Bougie, Ken Cheng, Nathan P. Coussens, Dorjbal Dorjsuren, Richard T. Eastman, Ruili Huang, Michael J. Iannotti, Surendra Karavadhi, Carleen Klumpp-Thomas, Jacob S. Roth, Srilatha Sakamuru, Wei Sun, Steven A. Titus, Adam Yasgar, Ya-Qin Zhang, Jinghua Zhao, Rodrigo B. Andrade, M. Kevin Brown, Robert B. Grossman
Canvass: A Crowd-Sourced, Natural-Product Screening Library For Exploring Biological Space, Sara E. Kearney, Gergely ZahoráNszky-KőHalmi, Kyle R. Brimacombe, Mark J. Henderson, Caitlin Lynch, Tongan Zhao, Kanny K. Wan, Zina Itkin, Christopher Dillon, Min Shen, Dorian M. Cheff, Tobie D. Lee, Danielle Bougie, Ken Cheng, Nathan P. Coussens, Dorjbal Dorjsuren, Richard T. Eastman, Ruili Huang, Michael J. Iannotti, Surendra Karavadhi, Carleen Klumpp-Thomas, Jacob S. Roth, Srilatha Sakamuru, Wei Sun, Steven A. Titus, Adam Yasgar, Ya-Qin Zhang, Jinghua Zhao, Rodrigo B. Andrade, M. Kevin Brown, Robert B. Grossman
Chemistry Faculty Publications
Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The …
Cysteine Modifiers Suggest An Allosteric Inhibitory Site On The Cal Pdz Domain, Yu Zhao, Patrick R. Cushing, David C. Smithson, Maria Pellegrini, Alexandre A. Pletnev, Sahar Al-Ayyoubi, Andrew V. Grassetti, Scott A. Gerber, R. Kiplin Guy, Dean R. Madden
Cysteine Modifiers Suggest An Allosteric Inhibitory Site On The Cal Pdz Domain, Yu Zhao, Patrick R. Cushing, David C. Smithson, Maria Pellegrini, Alexandre A. Pletnev, Sahar Al-Ayyoubi, Andrew V. Grassetti, Scott A. Gerber, R. Kiplin Guy, Dean R. Madden
Pharmaceutical Sciences Faculty Publications
Protein–protein interactions have become attractive targets for both experimental and therapeutic interventions. The PSD-95/Dlg1/ZO-1 (PDZ) domain is found in a large family of eukaryotic scaffold proteins that plays important roles in intracellular trafficking and localization of many target proteins. Here, we seek inhibitors of the PDZ protein that facilitates post-endocytic degradation of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR): the CFTR-associated ligand (CAL). We develop and validate biochemical screens and identify methyl-3,4-dephostatin (MD) and its analog ethyl-3,4-dephostatin (ED) as CAL PDZ inhibitors. Depending on conditions, MD can bind either covalently or non-covalently. Crystallographic and NMR data confirm that MD …
Agronomic And Chemical Performance Of Field-Grown Tobacco Engineered For Triterpene And Methylated Triterpene Metabolism, Zuodong Jiang, Chase Kempinski, Santosh Kumar, Scott Kinison, Kristin Linscott, Eric Nybo, Sarah Janze, Constance Wood, Joseph Chappell
Agronomic And Chemical Performance Of Field-Grown Tobacco Engineered For Triterpene And Methylated Triterpene Metabolism, Zuodong Jiang, Chase Kempinski, Santosh Kumar, Scott Kinison, Kristin Linscott, Eric Nybo, Sarah Janze, Constance Wood, Joseph Chappell
Pharmaceutical Sciences Faculty Publications
Squalene is a linear intermediate to nearly all classes of triterpenes and sterols and is itself highly valued for its use in wide range of industrial applications. Another unique linear triterpene is botryococcene and its methylated derivatives generated by the alga Botryococcus braunii race B, which are progenitors to fossil fuel deposits. Production of these linear triterpenes was previously engineered into transgenic tobacco by introducing the key steps of triterpene metabolism into the particular subcellular compartments. In this study, the agronomic characteristics (height, biomass accumulation, leaf area), the photosynthetic capacity (photosynthesis rate, conductance, internal CO2 levels) and triterpene content …
Abcg5 And Abcg8: More Than A Defense Against Xenosterols, Shailendra B. Patel, Gregory A. Graf, Ryan E. Temel
Abcg5 And Abcg8: More Than A Defense Against Xenosterols, Shailendra B. Patel, Gregory A. Graf, Ryan E. Temel
Pharmaceutical Sciences Faculty Publications
The elucidation of the molecular basis of the rare disease, sitosterolemia, has revolutionized our mechanistic understanding of how dietary sterols are excreted and how cholesterol is eliminated from the body. Two proteins, ABCG5 and ABCG8, encoded by the sitosterolemia locus, work as obligate dimers to pump sterols out of hepatocytes and enterocytes. ABCG5/ABCG8 are key in regulating whole-body sterol trafficking, by eliminating sterols via the biliary tree as well as the intestinal tract. Importantly, these transporters keep xenosterols from accumulating in the body. The sitosterolemia locus has been genetically associated with lipid levels and downstream atherosclerotic disease, as well as …
Informing Efforts To Develop Nitroreductase For Amine Production, Anne-Frances Miller, Jonathan T. Park, Kyle L. Ferguson, Warintra Pitsawong, Andreas S. Bommarius
Informing Efforts To Develop Nitroreductase For Amine Production, Anne-Frances Miller, Jonathan T. Park, Kyle L. Ferguson, Warintra Pitsawong, Andreas S. Bommarius
Chemistry Faculty Publications
Nitroreductases (NRs) hold promise for converting nitroaromatics to aromatic amines. Nitroaromatic reduction rate increases with Hammett substituent constant for NRs from two different subgroups, confirming substrate identity as a key determinant of reactivity. Amine yields were low, but compounds yielding amines tend to have a large π system and electron withdrawing substituents. Therefore, we also assessed the prospects of varying the enzyme. Several different subgroups of NRs include members able to produce aromatic amines. Comparison of four NR subgroups shows that they provide contrasting substrate binding cavities with distinct constraints on substrate position relative to the flavin. The unique architecture …
Structural Basis For Earp-Mediated Arginine Glycosylation Of Translation Elongation Factor Ef-P, Ralph Krafczyk, Jakub Macošek, Pravin Kumar Ankush Jagtap, Daniel Gast, Swetlana Wunder, Prithiba Mitra, Amit Kumar Jha, Jürgen Rohr, Anja Hoffmann-Röder, Kirsten Jung, Janosch Hennig, Jürgen Lassak
Structural Basis For Earp-Mediated Arginine Glycosylation Of Translation Elongation Factor Ef-P, Ralph Krafczyk, Jakub Macošek, Pravin Kumar Ankush Jagtap, Daniel Gast, Swetlana Wunder, Prithiba Mitra, Amit Kumar Jha, Jürgen Rohr, Anja Hoffmann-Röder, Kirsten Jung, Janosch Hennig, Jürgen Lassak
Pharmaceutical Sciences Faculty Publications
Glycosylation is a universal strategy to posttranslationally modify proteins. The recently discovered arginine rhamnosylation activates the polyproline-specific bacterial translation elongation factor EF-P. EF-P is rhamnosylated on arginine 32 by the glycosyltransferase EarP. However, the enzymatic mechanism remains elusive. In the present study, we solved the crystal structure of EarP from Pseudomonas putida. The enzyme is composed of two opposing domains with Rossmann folds, thus constituting a B pattern-type glycosyltransferase (GT-B). While dTDP-β-L-rhamnose is located within a highly conserved pocket of the C-domain, EarP recognizes the KOW-like N-domain of EF-P. Based on our data, we propose a structural model for …
Discovery Of A Diaminopyrimidine Flt3 Inhibitor Active Against Acute Myeloid Leukemia, Jamie A. Jarusiewicz, Jae Yoon Jeon, Michele C. Connelly, Yizhe Chen, Lei Yang, Sharyn D. Baker, R. Kiplin Guy
Discovery Of A Diaminopyrimidine Flt3 Inhibitor Active Against Acute Myeloid Leukemia, Jamie A. Jarusiewicz, Jae Yoon Jeon, Michele C. Connelly, Yizhe Chen, Lei Yang, Sharyn D. Baker, R. Kiplin Guy
Pharmaceutical Sciences Faculty Publications
Profiling of the kinase-binding capabilities of an aminopyrimidine analogue detected in a cellular screen of the St. Jude small-molecule collection led to the identification of a novel series of FMS-like tyrosine kinase 3 (FLT3) inhibitors. Structure–activity relationship studies led to the development of compounds exhibiting good potency against MV4-11 and MOLM13 acute myelogenous leukemia cells driven by FLT3, regardless of their FLT3 mutation status. In vitro pharmacological profiling demonstrated that compound 5e shows characteristics suitable for further preclinical development.
Oled Loki As A Catalyst For Tertiary Amine And Hydroxamate Glycosylation, Ryan R. Hughes, Khaled A. Shaaban, Jianjun Zhang, Hongnan Cao, George N. Phillips Jr., Jon S. Thorson
Oled Loki As A Catalyst For Tertiary Amine And Hydroxamate Glycosylation, Ryan R. Hughes, Khaled A. Shaaban, Jianjun Zhang, Hongnan Cao, George N. Phillips Jr., Jon S. Thorson
Center for Pharmaceutical Research and Innovation Faculty Publications
We describe the ability of an engineered glycosyltransferase (OleD Loki) to catalyze the N‐glycosylation of tertiary‐amine‐containing drugs and trichostatin hydroxamate glycosyl ester formation. As such, this study highlights the first bacterial model catalyst for tertiary‐amine N‐glycosylation and further expands the substrate scope and synthetic potential of engineered OleDs. In addition, this work could open the door to the discovery of similar capabilities among other permissive bacterial glycosyltransferases.
The Molecular Basis Of Talin2'S High Affinity Toward Β1-Integrin, Yaxia Yuan, Liqing Li, Yanyan Zhu, Lei Qi, Latifeh Azizi, Vesa P. Hytönen, Chang-Guo Zhan, Cai Huang
The Molecular Basis Of Talin2'S High Affinity Toward Β1-Integrin, Yaxia Yuan, Liqing Li, Yanyan Zhu, Lei Qi, Latifeh Azizi, Vesa P. Hytönen, Chang-Guo Zhan, Cai Huang
Molecular Modeling and Biopharmaceutical Center Faculty Publications
Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β–integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with …
An Arginine Finger Regulates The Sequential Action Of Asymmetrical Hexameric Atpase In The Double-Stranded Dna Translocation Motor, Zhengyi Zhao, Gian Marco De-Donatis, Chad T. Schwartz, Huaming Fang, Jingyuan Li, Peixuan Guo
An Arginine Finger Regulates The Sequential Action Of Asymmetrical Hexameric Atpase In The Double-Stranded Dna Translocation Motor, Zhengyi Zhao, Gian Marco De-Donatis, Chad T. Schwartz, Huaming Fang, Jingyuan Li, Peixuan Guo
Pharmaceutical Sciences Faculty Publications
Biological motors are ubiquitous in living systems. Currently, how the motor components coordinate the unidirectional motion is elusive in most cases. Here, we report that the sequential action of the ATPase ring in the DNA packaging motor of bacteriophage ϕ29 is regulated by an arginine finger that extends from one ATPase subunit to the adjacent unit to promote noncovalent dimer formation. Mutation of the arginine finger resulted in the interruption of ATPase oligomerization, ATP binding/hydrolysis, and DNA translocation. Dimer formation reappeared when arginine mutants were mixed with other ATPase subunits that can offer the arginine to promote their interaction. Ultracentrifugation …
Red-Shifted Aequorin Variants Incorporating Non-Canonical Amino Acids: Applications In In Vivo Imaging, Kristen M. Grinstead, Laura Rowe, Mark Ensor, Smita Joel, Pirouz Daftarian, Emre Dikici, Jean-Marc Zingg, Sylvia Daunert
Red-Shifted Aequorin Variants Incorporating Non-Canonical Amino Acids: Applications In In Vivo Imaging, Kristen M. Grinstead, Laura Rowe, Mark Ensor, Smita Joel, Pirouz Daftarian, Emre Dikici, Jean-Marc Zingg, Sylvia Daunert
Pharmaceutical Sciences Faculty Publications
The increased importance of in vivo diagnostics has posed new demands for imaging technologies. In that regard, there is a need for imaging molecules capable of expanding the applications of current state-of-the-art imaging in vivo diagnostics. To that end, there is a desire for new reporter molecules capable of providing strong signals, are non-toxic, and can be tailored to diagnose or monitor the progression of a number of diseases. Aequorin is a non-toxic photoprotein that can be used as a sensitive marker for bioluminescence in vivo imaging. The sensitivity of aequorin is due to the fact that bioluminescence is a …
The Hiv-1 Tat Protein Is Monomethylated At Lysine 71 By The Lysine Methyltransferase Kmt7, Ibraheem Ali, Holly Ramage, Daniela Boehm, Lynnette M. A. Dirk, Naoki Sakane, Kazuki Hanada, Sara Pagans, Katrin Kaehlcke, Katherine Aull, Leor Weinberger, Raymond Trievel, Martina Schnoelzer, Masafumi Kamada, Robert L. Houtz, Melanie Ott
The Hiv-1 Tat Protein Is Monomethylated At Lysine 71 By The Lysine Methyltransferase Kmt7, Ibraheem Ali, Holly Ramage, Daniela Boehm, Lynnette M. A. Dirk, Naoki Sakane, Kazuki Hanada, Sara Pagans, Katrin Kaehlcke, Katherine Aull, Leor Weinberger, Raymond Trievel, Martina Schnoelzer, Masafumi Kamada, Robert L. Houtz, Melanie Ott
Horticulture Faculty Publications
The HIV-1 transactivator protein Tat is a critical regulator of HIV transcription primarily enabling efficient elongation of viral transcripts. Its interactions with RNA and various host factors are regulated by ordered, transient post-translational modifications. Here, we report a novel Tat modification, monomethylation at lysine 71 (K71). We found that Lys-71 monomethylation (K71me) is catalyzed by KMT7, a methyltransferase that also targets lysine 51 (K51) in Tat. Using mass spectrometry, in vitro enzymology, and modification-specific antibodies, we found that KMT7 monomethylates both Lys-71 and Lys-51 in Tat. K71me is important for full Tat transactivation, as KMT7 knockdown impaired the transcriptional activity …
Steroid Binding To Autotaxin Links Bile Salts And Lysophosphatidic Acid Signalling, Willem-Jan Keune, Jens Hausmann, Ruth Bolier, Dagmar Tolenaars, Andreas Kremer, Tatjana Heidebrecht, Robbie P. Joosten, Manjula Sunkara, Andrew J. Morris, Elisa Matas-Rico, Wouter H. Moolenaar, Ronald P. Oude Elferink, Anastassis Perrakis
Steroid Binding To Autotaxin Links Bile Salts And Lysophosphatidic Acid Signalling, Willem-Jan Keune, Jens Hausmann, Ruth Bolier, Dagmar Tolenaars, Andreas Kremer, Tatjana Heidebrecht, Robbie P. Joosten, Manjula Sunkara, Andrew J. Morris, Elisa Matas-Rico, Wouter H. Moolenaar, Ronald P. Oude Elferink, Anastassis Perrakis
Gill Heart & Vascular Institute Faculty Publications
Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors …
Data Publication With The Structural Biology Data Grid Supports Live Analysis, Peter A. Meyer, Stephanie Socias, Jason Key, Elizabeth Ransey, Emily C. Tjon, Alejandro Buschiazzo, Ming Lei, Chris Botka, James Withrow, David Neau, Kanagalaghatta Rajashankar, Karen S. Anderson, Richard H. Baxter, Stephen C. Blacklow, Titus J. Boggon, Alexandre M. J. J. Bonvin, Dominika Borek, Tom J. Brett, Amedeo Caflisch, Chung-I Chang, Walter J. Chazin, Kevin D. Corbett, Michael S. Cosgrove, Sean Crosson, Sirano Dhe-Paganon, Enrico Di Cera, Catherine L. Drennan, Michael J. Eck, Brandt F. Eichman, Qing R. Fan, Oleg V. Tsodikov
Data Publication With The Structural Biology Data Grid Supports Live Analysis, Peter A. Meyer, Stephanie Socias, Jason Key, Elizabeth Ransey, Emily C. Tjon, Alejandro Buschiazzo, Ming Lei, Chris Botka, James Withrow, David Neau, Kanagalaghatta Rajashankar, Karen S. Anderson, Richard H. Baxter, Stephen C. Blacklow, Titus J. Boggon, Alexandre M. J. J. Bonvin, Dominika Borek, Tom J. Brett, Amedeo Caflisch, Chung-I Chang, Walter J. Chazin, Kevin D. Corbett, Michael S. Cosgrove, Sean Crosson, Sirano Dhe-Paganon, Enrico Di Cera, Catherine L. Drennan, Michael J. Eck, Brandt F. Eichman, Qing R. Fan, Oleg V. Tsodikov
Pharmaceutical Sciences Faculty Publications
Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models and indispensable for development of structural biology processing methods. Here, we established a diffraction data publication and dissemination system, Structural Biology Data Grid (SBDG; data.sbgrid.org), to preserve primary experimental data sets that support scientific publications. Data sets are accessible to researchers through a community driven data grid, which facilitates global data access. Our analysis of a pilot collection of crystallographic data sets demonstrates that the information archived by SBDG is sufficient to reprocess data to statistics that meet or exceed the quality of the …
Biological Nanomotors With A Revolution, Linear, Or Rotation Motion Mechanism, Peixuan Guo, Hiroyuki Noji, Christopher M. Yengo, Zhengyi Zhao, Ian Grainge
Biological Nanomotors With A Revolution, Linear, Or Rotation Motion Mechanism, Peixuan Guo, Hiroyuki Noji, Christopher M. Yengo, Zhengyi Zhao, Ian Grainge
Nanobiotechnology Center Faculty Publications
The ubiquitous biological nanomotors were classified into two categories in the past: linear and rotation motors. In 2013, a third type of biomotor, revolution without rotation (http://rnanano.osu.edu/movie.html), was discovered and found to be widespread among bacteria, eukaryotic viruses, and double-stranded DNA (dsDNA) bacteriophages. This review focuses on recent findings about various aspects of motors, including chirality, stoichiometry, channel size, entropy, conformational change, and energy usage rate, in a variety of well-studied motors, including FoF1 ATPase, helicases, viral dsDNA-packaging motors, bacterial chromosome translocases, myosin, kinesin, and dynein. In particular, dsDNA translocases are used to illustrate how …
Targeting An Essential Gtpase Obg For The Development Of Broad-Spectrum Antibiotics, Josephine A. Bonventre, Ryszard A. Zielke, Konstantin V. Korotkov, Aleksandra E. Sikora
Targeting An Essential Gtpase Obg For The Development Of Broad-Spectrum Antibiotics, Josephine A. Bonventre, Ryszard A. Zielke, Konstantin V. Korotkov, Aleksandra E. Sikora
Molecular and Cellular Biochemistry Faculty Publications
A promising new drug target for the development of novel broad-spectrum antibiotics is the highly conserved small GTPase Obg (YhbZ, CgtA), a protein essential for the survival of all bacteria including Neisseria gonorrhoeae (GC). GC is the agent of gonorrhea, a prevalent sexually transmitted disease resulting in serious consequences on reproductive and neonatal health. A preventive anti-gonorrhea vaccine does not exist, and options for effective antibiotic treatments are increasingly limited. To address the dire need for alternative antimicrobial strategies, we have designed and optimized a 384-well GTPase assay to identify inhibitors of Obg using as a model Obg protein from …
The Influence Of Citrate, Maltolate And Fluoride On The Gastrointestinal Absorption Of Aluminum At A Drinking Water-Relevant Concentration: A 26Al And 14C Study, Yuzhao Zhou, Wesley R. Harris, Robert A. Yokel
The Influence Of Citrate, Maltolate And Fluoride On The Gastrointestinal Absorption Of Aluminum At A Drinking Water-Relevant Concentration: A 26Al And 14C Study, Yuzhao Zhou, Wesley R. Harris, Robert A. Yokel
Pharmaceutical Sciences Faculty Publications
The objectives were to test the null hypotheses that (1) citrate, maltolate, and fluoride do not significantly influence oral Al bioavailability, Cmax or Tmax at an Al dose relevant to drinking water exposure; and (2) Al citrate and maltolate are absorbed intact from the gastrointestinal tract. Male Fisher rats were given 1 ml of solution intra-gastrically containing 1 nCi 26Al (65 nmol total Al) as the Al3+ ion, or as complexes with 14C-citrate, 14C-maltolate or fluoride, during concurrent 27Al iv infusion. Blood was repeatedly collected for serum 26Al, total Al and 14 …
Novel Function Of Phosphoinositide 3-Kinase In T Cell Ca2+ Signaling, Ao-Lin Hsu, Tsui-Ting Ching, Goutam Sen, Da-Sheng Wan, Subbarao Bondada, Kalwant S. Authi, Ching-Shih Chen
Novel Function Of Phosphoinositide 3-Kinase In T Cell Ca2+ Signaling, Ao-Lin Hsu, Tsui-Ting Ching, Goutam Sen, Da-Sheng Wan, Subbarao Bondada, Kalwant S. Authi, Ching-Shih Chen
Pharmaceutical Sciences Faculty Publications
This study presents evidence that phosphoinositide (PI) 3-kinase is involved in T cell Ca2+ signaling via a phosphatidylinositol 3,4,5-trisphosphate PI(3,4,5)P3-sensitive Ca2+entry pathway. First, exogenous PI(3,4,5)P3 at concentrations close to its physiological levels induces Ca2+ influx in T cells, whereas PI(3,4)P2, PI(4,5)P2, and PI(3)P have no effect on [Ca2+]i. This Ca2+ entry mechanism is cell type-specific as B cells and a number of cell lines examined do not respond to PI(3,4,5)P3 stimulation. Second, inhibition of PI 3-kinase by wortmannin and by overexpression of the …