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https://www.readbyqxmd.com/read/28544448/using-pymol-to-explore-the-effects-of-ph-on-noncovalent-interactions-between-immunoglobulin-g-and-protein-a-a-guided-inquiry-biochemistry-activity
#1
Zahilyn D Roche Allred, Heeyoung Tai, Stacey Lowery Bretz, Richard C Page
Students' understandings of foundational concepts such as noncovalent interactions, pH and pKa are crucial for success in undergraduate biochemistry courses. We developed a guided-inquiry activity to aid students in making connections between noncovalent interactions and pH/pKa . Students explore these concepts by examining the primary and tertiary structures of immunoglobulin G (IgG) and Protein A. Students use PyMOL, an open source molecular visualization application, to (1) identify hydrogen bonds and salt bridges between and within the proteins at physiological pH and (2) apply their knowledge of pH/pKa to association rate constant data for these proteins at pH 4 and pH 11...
May 24, 2017: Biochemistry and Molecular Biology Education
https://www.readbyqxmd.com/read/28544090/functional-tuning-of-the-catalytic-residue-pka-in-a-de-novo-designed-esterase
#2
Katharina Hiebler, Zsófia Lengyel, Carlos A Castañeda, Olga V Makhlynets
AlleyCatE is a de novo designed esterase that can be allosterically regulated by calcium ions. This artificial enzyme has been shown to hydrolyze p-nitrophenyl acetate (pNPA) and 4-nitrophenyl-(2-phenyl)-propanoate (pNPP) with high catalytic efficiency. AlleyCatE was created by introducing a single histidine residue (His(144) ) into a hydrophobic pocket of calmodulin. In this work, we explore the determinants of catalytic properties of AlleyCatE. We obtained the pKa value of the catalytic histidine using experimental measurements by NMR and pH rate profile and compared these values to those predicted from electrostatics pKa calculations (from both empirical and continuum electrostatics calculations)...
May 24, 2017: Proteins
https://www.readbyqxmd.com/read/28544028/subcellular-compartmentation-interdependency-and-dynamics-of-the-cyclic-amp-dependent-pka-subunits-during-pathogenic-differentiation-in-rice-blast
#3
Poonguzhali Selvaraj, Tham Hong Fai, Ravikrishna Ramanujam, Naweed I Naqvi
The cAMP-dependent PKA signaling plays a central role in growth, asexual development and pathogenesis in fungal pathogens. Here, we functionally characterized RPKA, the regulatory subunit of cAMP/PKA and studied the dynamics and organization of the PKA subunits in the rice blast pathogen Magnaporthe oryzae. The RPKA subunit was essential for proper vegetative growth, asexual sporulation and surface hydrophobicity in M. oryzae. A spontaneous suppressor mutation, SMR19, that restored growth and conidiation in the RPKA deletion mutant was isolated and characterized...
May 20, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28542501/a-rho-associated-coiled-coil-containing-kinases-rock-inhibitor-y-27632-enhances-adhesion-viability-and-differentiation-of-human-term-placenta-derived-trophoblasts-in-vitro
#4
Kenichiro Motomura, Naoko Okada, Hideaki Morita, Mariko Hara, Masato Tamari, Keisuke Orimo, Go Matsuda, Ken-Ichi Imadome, Akio Matsuda, Takeshi Nagamatsu, Mikiya Fujieda, Haruhiko Sago, Hirohisa Saito, Kenji Matsumoto
Although human term placenta-derived primary cytotrophoblasts (pCTBs) represent a good human syncytiotrophoblast (STB) model, in vitro culture of pCTBs is not always easily accomplished. Y-27632, a specific inhibitor of Rho-associated coiled-coil containing kinases (ROCK), reportedly prevented apoptosis and improved cell-to-substrate adhesion and culture stability of dissociated cultured human embryonic stem cells and human corneal endothelial cells. The Rho kinase pathway regulates various kinds of cell behavior, some of which are involved in pCTB adhesion and differentiation...
2017: PloS One
https://www.readbyqxmd.com/read/28538148/active-site-pka-determination-for-photoactive-yellow-protein-rationalizes-slow-ground-state-recovery
#5
Nur Alia Oktaviani, Trijntje J Pool, Yuichi Yoshimura, Hironari Kamikubo, Ruud M Scheek, Mikio Kataoka, Frans A A Mulder
The ability to avoid blue-light radiation is crucial for bacteria to survive. In Halorhodospira halophila, the putative receptor for this response is known as photoactive yellow protein (PYP). Its response to blue light is mediated by changes in the optical properties of the chromophore para-coumaric acid (pCA) in the protein active site. PYP displays photocycle kinetics with a strong pH dependence for ground-state recovery, which has remained enigmatic. To resolve this problem, a comprehensive pKa determination of the active-site residues of PYP is required...
May 23, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28536714/systematic-investigation-of-protein-kinase-a-substrate-proteins-using-on-chip-protein-kinase-kinetic-profiling
#6
Se-Hui Jung, Deok-Hoon Kong, Hye-Yoon Jeon, Eun-Taek Han, Won Sun Park, Seok-Ho Hong, Young-Myeong Kim, Kwon-Soo Ha
Protein kinases play a critical role in a wide variety of cellular processes through post-translational protein phosphorylation and identification of their substrate proteins is important for understanding the enzymes' mechanism of action and elucidating their functions in physiological and disease processes. However, there have been few systematic investigations of protein kinase substrates due to a lack of high-throughput kinetic assays. Thus, we designed an on-chip protein kinase assay for profiling kinase kinetic parameters by introducing the phosphorylation rate (Vp) under physiological conditions, instead of the maximal velocity (Vmax), in a high-throughput manner...
May 24, 2017: Analyst
https://www.readbyqxmd.com/read/28535993/structural-basis-for-asymmetric-conductance-of-the-influenza-m2-proton-channel-investigated-by-solid-state-nmr-spectroscopy
#7
Venkata S Mandala, Shu Yu Liao, Byungsu Kwon, Mei Hong
The influenza M2 protein forms an acid-activated proton channel that is essential for virus replication. The transmembrane H37 selects for protons under low external pH (pHout) while W41 ensures proton conduction only from the N-terminus to the C-terminus and prevents reverse current under low internal pH (pHin). Here we address the molecular basis for this asymmetric conduction by investigating the structure and dynamics of a mutant channel, W41F, which permits reverse current under low pHin. Solid-state NMR experiments show that W41F M2 retains the pH-dependent α-helical conformations and tetrameric structure of the wild-type channel, but has significantly altered protonation and tautomeric equilibria at H37...
May 20, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28534087/interspecies-differences-in-pth-mediated-pka-phosphorylation-of-the-epithelial-calcium-channel-trpv5
#8
Mark K van Goor, Sjoerd Verkaart, Teunis J van Dam, Martijn A Huynen, Jenny van der Wijst
The epithelial calcium (Ca(2+)) channel TRPV5 (transient receptor potential vanilloid 5) is expressed in the distal convoluted tubule of the kidney and facilitates active Ca(2+) reabsorption. This process is instrumental for the maintenance of Ca(2+) homeostasis. Therefore, all aspects of TRPV5 function are tightly regulated by the calciotropic parathyroid hormone (PTH). Rabbit (rb)TRPV5 channel activity was shown to be stimulated upon PTH-mediated protein kinase A (PKA) phosphorylation. Since there is incomplete conservation of the PKA consensus motif (RR/QxT) across species, the aim of this study was to extend these findings to humans and characterize the expression and function of human (h)TRPV5...
May 22, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28533546/prostaglandin-e2-inhibits-matrix-mineralization-by-human-bone-marrow-stromal-cell-derived-osteoblasts-via-epac-dependent-camp-signaling
#9
Ali Mirsaidi, André N Tiaden, Peter J Richards
The osteoinductive properties of prostaglandin E2 (PGE2) and its signaling pathways have led to suggestions that it may serve as a potential therapeutic strategy for bone loss. However, the prominence of PGE2 as an inducer of bone formation is attributed primarily to findings from studies using rodent models. In the current study, we investigated the effects of PGE2 on human bone marrow stromal cell (hBMSC) lineage commitment and determined its mode of action. We demonstrated that PGE2 treatment of hBMSCs significantly altered the expression profile of several genes associated with osteoblast differentiation (RUNX2 and ALP) and maturation (BGLAP and MGP)...
May 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28530384/divalent-metal-ion-activation-of-a-guanine-general-base-in-the-hammerhead-ribozyme-insights-from-molecular-simulations
#10
Haoyuan Chen, Timothy J Giese, Barbara L Golden, Darrin M York
The hammerhead ribozyme is a well-studied nucleolytic ribozyme that catalyzes the self-cleavage of the RNA phosphodiester backbone. Despite experimental and theoretical efforts, there remain key questions about details of the mechanism with regard to the activation of the nucleophile by the putative general base guanine (G12). Straight-forward interpretation of the measured activity-pH data implies the pKa value of the N1 position in the G12 nucleobase is significantly shifted by the ribozyme environment. Recent crystallographic and biochemical work has identified pH-dependent divalent metal ion binding at the N7/O6 position of G12, leading to the hypothesis that this binding mode could induce a pKa shift of G12 towards neutrality...
May 22, 2017: Biochemistry
https://www.readbyqxmd.com/read/28529629/the-antihelminthic-drug-niclosamide-effectively-inhibits-the-malignant-phenotypes-of-uveal-melanoma-in-vitro-and-in-vivo
#11
Jingfeng Zhou, Bei Jin, Yanli Jin, Yizhi Liu, Jingxuan Pan
Uveal melanoma (UM) is a lethal intraocular malignancy with an average survival of only 2~8 months in patients with hepatic metastasis. Currently, there is no effective therapy for metastatic UM. Here, we reported that niclosamide, an effective repellence of tapeworm that has been approved for use in patients for approximately 50 years, exhibited strong antitumor activity in UM cells in vitro and in vivo. We showed that niclosamide potently inhibited UM cell proliferation, induced apoptosis and reduced migration and invasion...
2017: Theranostics
https://www.readbyqxmd.com/read/28528970/the-many-faces-of-compartmentalized-pka-signalosomes
#12
REVIEW
Omar Torres-Quesada, Johanna E Mayrhofer, Eduard Stefan
Cellular signal transmission requires the dynamic formation of spatiotemporally controlled molecular interactions. At the cell surface information is received by receptor complexes and relayed through intracellular signaling platforms which organize the actions of functionally interacting signaling enzymes and substrates. The list of hormone or neurotransmitter pathways that utilize the ubiquitous cAMP-sensing protein kinase A (PKA) system is expansive. This requires that the specificity, duration, and intensity of PKA responses are spatially and temporally restricted...
May 18, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28528876/modeling-covalent-modifier-drugs
#13
REVIEW
Ernest Awoonor-Williams, Andrew G Walsh, Christopher N Rowley
In this review, we present a summary of how computer modeling has been used in the development of covalent modifier drugs. Covalent modifier drugs bind by forming a chemical bond with their target. This covalent binding can improve the selectivity of the drug for a target with complementary reactivity and result in increased binding affinities due to the strength of the covalent bond formed. In some cases, this results in irreversible inhibition of the target, but some targeted covalent inhibitor (TCI) drugs bind covalently but reversibly...
May 18, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28528353/adrenomedullin-ameliorates-podocyte-injury-induced-by-puromycin-aminonucleoside-in-vitro-and-in-vivo-through-modulation-of-rho-gtpases
#14
Nan Dong, Lixia Meng, Ruqun Xue, Meng Yu, Zhonghua Zhao, Xueguang Liu
PURPOSE: Podocyte injury is a key event in proteinuric kidney disease and eventually glomerular scarring. While adrenomedullin (AM), a potent vasodilatory peptide, has been reported to confer renoprotection in several experimental models of kidney diseases, its effect on injured podocytes and the related mechanism is still largely unknown. METHODS: Employing Western blotting analysis, immunoprecipitation and immunofluorescence, we investigated the effects of AM on the expressions of podocyte cytoskeletal proteins and Rho-family small GTPases (Rho GTPases) in puromycin aminonucleoside (PAN)-induced podocyte injury, both in cultured podocytes and in PAN nephrosis rats...
May 20, 2017: International Urology and Nephrology
https://www.readbyqxmd.com/read/28525892/rasal1-is-a-potent-regulator-of-hepatic-stellate-cell-activity-and-liver-fibrosis
#15
Akemi Takata, Motoyuki Otsuka, Takahiro Kishikawa, Mari Yamagami, Rei Ishibashi, Kazuma Sekiba, Tatsunori Suzuki, Motoko Ohno, Yui Yamashita, Takaya Abe, Ryota Masuzaki, Tsuneo Ikenoue, Kazuhiko Koike
Liver fibrosis, leading to cirrhosis and liver failure, can occur after chronic liver injury. The transition of hepatic stellate cells (HSCs) from quiescent cells into proliferative and fibrogenic cells is a central event in liver fibrosis. Here, we show that RAS protein activator like-1 (RASAL1), a RAS-GTPase-activating protein, which switches off RAS activity, is significantly decreased during HSC activation, and that HSC activation can be antagonized by forced expression of the RASAL1 protein. We demonstrate that RASAL1 suppresses HSC proliferation by regulating the Ras-MAPK pathway, and that RASAL1 suppresses HSC fibrogenic activity by regulating the PKA-LKB1-AMPK-SRF pathway by interacting with angiotensin II receptor, type 1...
May 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28523354/investigation-of-reference-levels-and-radiation-dose-associated-with-abdominal-evar-endovascular-aneurysm-repair-procedures-across-several-european-centres
#16
E Tuthill, L O'Hora, M O'Donohoe, S Panci, P Gilligan, D Campion, R Trenti, E Fox, D Catania, L Rainford
OBJECTIVES: Endovascular aneurysm repair (EVAR) is considered the treatment of choice for abdominal aortic aneurysms with suitable anatomy. In order to improve radiation safety, European Directive (2013/59) requires member states to implement diagnostic reference levels (DRLs) in radio-diagnostic and interventional procedures. This study aimed to determine local DRLs for EVAR across five European centres and identify an interim European DRL, which currently remains unestablished. METHODS: Retrospective data was collected for 180 standard EVARs performed between January 2014 and July 2015 from five specialist centres in Ireland (n=2) and Italy (n=3)...
May 18, 2017: European Radiology
https://www.readbyqxmd.com/read/28523193/mechanisms-underlying-the-antidepressant-response-of-acupuncture-via-pka-creb-signaling-pathway
#17
Huili Jiang, Xuhui Zhang, Yu Wang, Huimin Zhang, Jing Li, Xinjing Yang, Bingcong Zhao, Chuntao Zhang, Miao Yu, Mingmin Xu, Qiuyun Yu, Xingchen Liang, Xiang Li, Peng Shi, Tuya Bao
Protein kinase A (PKA)/cAMP response element-binding (CREB) protein signaling pathway, contributing to impaired neurogenesis parallel to depressive-like behaviors, has been identified as the crucial factor involved in the antidepressant response of acupuncture. However, the molecular mechanisms associated with antidepressant response of acupuncture, neurogenesis, and depressive-like behaviors ameliorating remain unexplored. The objective was to identify the mechanisms underlying the antidepressant response of acupuncture through PKA signaling pathway in depression rats by employing the PKA signaling pathway inhibitor H89 in in vivo experiments...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28521061/extracellular-camp-activates-molecular-signalling-pathways-associated-with-sperm-capacitation-in-bovines
#18
Carlos Agustín I Alonso, Claudia E Osycka-Salut, Luciana Castellano, Andreína Cesari, Nicolás Di Siervi, Adrián Mutto, Anders Johannisson, Jane M Morrell, Carlos Davio, Silvina Perez-Martinez
STUDY QUESTION: Is extracellular cAMP involved in the regulation of signalling pathways in bovine sperm capacitation? SUMMARY ANSWER: Extracellular cAMP-induced sperm capacitation through the activation of different signalling pathways that involve phospholipase C (PLC), PKC/ERK1-2 signalling and an increase in sperm Ca2+ levels, as well as soluble AC and cAMP/protein kinase A (PKA) signalling. WHAT IS KNOWN ALREADY: In order to fertilize the oocyte, ejaculated spermatozoa must undergo a series of changes in the female reproductive tract, known as capacitation...
May 18, 2017: Molecular Human Reproduction
https://www.readbyqxmd.com/read/28520415/design-and-synthesis-of-soluble-and-cell-permeable-pi3k%C3%AE-inhibitors-for-long-acting-inhaled-administration
#19
Matthew W D Perry, Karin Björhall, Britta K Bonn, Johan Carlsson, Yunhua Chen, Anders Eriksson, Linda Fredlund, Hai'e Hao, Neil S Holden, Kostas Karabelas, Helena Lindmark, Feifei Liu, Nils Pemberton, Jens Petersen, Sandra Rodrigo Blomqvist, Reed W Smith, Tor Svensson, Ina Terstiege, Christian Tyrchan, Wenzhen Yang, Shuchun Zhao, Linda Öster
PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesised to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimisation for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation...
May 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28518188/ph-dependent-absorption-spectrum-of-a-protein-a-minimal-electrostatic-model-of-anabaena-sensory-rhodopsin
#20
Michael Stenrup, Elisa Pieri, Vincent Ledentu, Nicolas Ferré
A minimal electrostatic model is introduced which aims at reproducing and analyzing the visible-light absorption energy shift of a protein with pH. It relies on the existence of a protein structure, the prediction of titratable amino-acid pKa values and a very limited set of parameters. Applied to the case of the photochromic Anabaena sensory rhodopsin protein, the model succeeds in reproducing qualitatively the reported experimental data, confirming the importance of aspartic acid 217 in the observed blue shift in the λmax of ASR at neutral pH...
May 18, 2017: Physical Chemistry Chemical Physics: PCCP
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