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Mark sansom

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https://www.readbyqxmd.com/read/27881707/a-cd80-biased-ctla4-ig-fusion-protein-with-superior-in-vivo-efficacy-by-simultaneous-engineering-of-affinity-selectivity-stability-and-fcrn-binding
#1
Julie Douthwaite, Jacques Moisan, Cyril Privezentzev, Blagoje Soskic, Shereen Sabbah, Suzanne Cohen, Andie Collinson, Elizabeth England, Catherine Huntington, Ben Kemp, Li Zhuang, Suzanne Hudak, D Gareth Rees, Debbie Goldberg, Chris Barton, Linda Chang, Inna Vainshtein, Meina Liang, Laurie Iciek, Philip Ambery, Mark Peakman, Tristan J Vaughan, Tim I M Tree, David M Sansom, Michael A Bowen, Ralph R Minter, Lutz Jermutus
Affinity- and stability-engineered variants of CTLA4-Ig fusion molecules with enhanced pharmacokinetic profiles could yield improved therapies with the potential of higher efficacy and greater convenience to patients. In this study, to our knowledge, we have, for the first time, used in vitro evolution to simultaneously optimize CTLA4 affinity and stability. We selected for improved binding to both ligands, CD80 and CD86, and screened as dimeric Fc fusions directly in functional assays to identify variants with stronger suppression of in vitro T cell activation...
November 23, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27866853/functional-annotation-of-ion-channel-structures-by-molecular-simulation
#2
Jemma L Trick, Sivapalan Chelvaniththilan, Gianni Klesse, Prafulla Aryal, E Jayne Wallace, Stephen J Tucker, Mark S P Sansom
Ion channels play key roles in cell membranes, and recent advances are yielding an increasing number of structures. However, their functional relevance is often unclear and better tools are required for their functional annotation. In sub-nanometer pores such as ion channels, hydrophobic gating has been shown to promote dewetting to produce a functionally closed (i.e., non-conductive) state. Using the serotonin receptor (5-HT3R) structure as an example, we demonstrate the use of molecular dynamics to aid the functional annotation of channel structures via simulation of the behavior of water within the pore...
November 8, 2016: Structure
https://www.readbyqxmd.com/read/27856273/hypermutation-in-pancreatic-cancer
#3
Jeremy L Humphris, Ann-Marie Patch, Katia Nones, Peter J Bailey, Amber L Johns, Skye McKay, David K Chang, David K Miller, Marina Pajic, Karin S Kassahn, Michael C J Quinn, Timothy J C Bruxner, Angelika N Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan Nourbakhsh, Andrew Stone, Peter J Wilson, Matthew Anderson, J Lynn Fink, Oliver Holmes, Stephen Kazakoff, Conrad Leonard, Felicity Newell, Nick Waddell, Scott Wood, Ronald S Mead, Qinying Xu, Jianmin Wu, Mark Pinese, Mark J Cowley, Marc D Jones, Adnan M Nagrial, Venessa T Chin, Lorraine A Chantrill, Amanda Mawson, Angela Chou, Christopher J Scarlett, Andreia V Pinho, Ilse Rooman, Marc Giry-Laterriere, Jaswinder S Samra, James G Kench, Neil D Merrett, Christopher W Toon, Krishna Epari, Nam Q Nguyen, Andrew Barbour, Nikolajs Zeps, Nigel B Jamieson, Colin J McKay, C Ross Carter, Euan J Dickson, Janet S Graham, Fraser Duthie, Karin Oien, Jane Hair, Jennifer P Morton, Owen J Sansom, Robert Grützmann, Ralph H Hruban, Anirban Maitra, Christine A Iacobuzio-Donahue, Richard D Schulick, Christopher L Wolfgang, Richard A Morgan, Rita T Lawlor, Borislav Rusev, Vincenzo Corbo, Roberto Salvia, Ivana Cataldo, Giampaolo Tortora, Margaret A Tempero, Oliver Hofmann, James R Eshleman, Christian Pilarsky, Aldo Scarpa, Elizabeth A Musgrove, Anthony J Gill, John V Pearson, Sean M Grimmond, Nicola Waddell, Andrew V Biankin
Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2...
November 15, 2016: Gastroenterology
https://www.readbyqxmd.com/read/27807980/convergence-and-sampling-in-determining-free-energy-landscapes-for-membrane-protein-association
#4
Jan Domanski, George Hedger, Robert B Best, Phillip James Stansfeld, Mark S P Sansom
Potential of mean force (PMF) calculations are used to characterize the free energy landscape of protein-lipid and protein-protein association within membranes. Coarse-grained simulations allow binding free energies to be determined with reasonable statistical error. This accuracy relies on defining a good collective variable describing the binding and unbinding transition, and upon criteria for assessing the convergence of the simulation toward representative equilibrium sampling. As examples, we calculate protein-lipid binding PMFs for ANT/cardiolipin and Kir2...
November 3, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27786441/lipid-loving-ants-molecular-simulations-of-cardiolipin-interactions-and-the-organization-of-the-adenine-nucleotide-translocase-in-model-mitochondrial-membranes
#5
George Hedger, Sarah L Rouse, Jan Domanski, Matthieu Chavent, Heidi Koldsø, Mark S P Sansom
The exchange of ADP and ATP across the inner mitochondrial membrane is a fundamental cellular process. This exchange is facilitated by the adenine nucleotide translocase (ANT), the structure and function of which is critically dependent on the signature phospholipid of mitochondria, cardiolipin (CL). Here we employ multiscale molecular dynamics simulations to investigate CL interactions within a membrane environment. Using simulations at both coarse-grained (CG) and atomistic (AT) resolutions, we identify three CL binding sites on the translocase, in agreement with those seen in crystal structures and inferred from NMR measurements...
October 27, 2016: Biochemistry
https://www.readbyqxmd.com/read/27722554/membrane-stiffness-is-modified-by-integral-membrane-proteins
#6
Philip W Fowler, Jean Hélie, Anna Duncan, Matthieu Chavent, Heidi Koldsø, Mark S P Sansom
The ease with which a cell membrane can bend and deform is important for a wide range of biological functions. Peripheral proteins that induce curvature in membranes (e.g. BAR domains) have been studied for a number of years. Little is known, however, about the effect of integral membrane proteins on the stiffness of a membrane (characterised by the bending rigidity, Kc). We demonstrate by computer simulation that adding integral membrane proteins at physiological densities alters the stiffness of the membrane...
September 20, 2016: Soft Matter
https://www.readbyqxmd.com/read/27574865/roles-of-interleaflet-coupling-and-hydrophobic-mismatch-in-lipid-membrane-phase-separation-kinetics
#7
Philip W Fowler, John J Williamson, Mark S P Sansom, Peter D Olmsted
Characterizing the nanoscale dynamic organization within lipid bilayer membranes is central to our understanding of cell membranes at a molecular level. We investigate phase separation and communication across leaflets in ternary lipid bilayers, including saturated lipids with between 12 and 20 carbons per tail. Coarse-grained molecular dynamics simulations reveal a novel two-step kinetics due to hydrophobic mismatch, in which the initial response of the apposed leaflets upon quenching is to increase local asymmetry (antiregistration), followed by dominance of symmetry (registration) as the bilayer equilibrates...
September 14, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27572256/proton-currents-constrain-structural-models-of-voltage-sensor-activation
#8
Aaron L Randolph, Younes Mokrab, Ashley L Bennett, Mark Sp Sansom, Ian Scott Ramsey
The Hv1 proton channel is evidently unique among voltage sensor domain proteins in mediating an intrinsic 'aqueous' H(+) conductance (GAQ). Mutation of a highly conserved 'gating charge' residue in the S4 helix (R1H) confers a resting-state H(+) 'shuttle' conductance (GSH) in VGCs and Ci VSP, and we now report that R1H is sufficient to reconstitute GSH in Hv1 without abrogating GAQ. Second-site mutations in S3 (D185A/H) and S4 (N4R) experimentally separate GSH and GAQ gating, which report thermodynamically distinct initial and final steps, respectively, in the Hv1 activation pathway...
August 30, 2016: ELife
https://www.readbyqxmd.com/read/27488650/pigmented-anatomy-in-carboniferous-cyclostomes-and-the-evolution-of-the-vertebrate-eye
#9
Sarah E Gabbott, Philip C J Donoghue, Robert S Sansom, Jakob Vinther, Andrei Dolocan, Mark A Purnell
The success of vertebrates is linked to the evolution of a camera-style eye and sophisticated visual system. In the absence of useful data from fossils, scenarios for evolutionary assembly of the vertebrate eye have been based necessarily on evidence from development, molecular genetics and comparative anatomy in living vertebrates. Unfortunately, steps in the transition from a light-sensitive 'eye spot' in invertebrate chordates to an image-forming camera-style eye in jawed vertebrates are constrained only by hagfish and lampreys (cyclostomes), which are interpreted to reflect either an intermediate or degenerate condition...
August 17, 2016: Proceedings. Biological Sciences
https://www.readbyqxmd.com/read/27465729/the-integrin-receptor-in-biologically-relevant-bilayers-insights-from-molecular-dynamics-simulations
#10
Antreas C Kalli, Tomasz Rog, Ilpo Vattulainen, Iain D Campbell, Mark S P Sansom
Integrins are heterodimeric (αβ) cell surface receptors that are potential therapeutic targets for a number of diseases. Despite the existence of structural data for all parts of integrins, the structure of the complete integrin receptor is still not available. We have used available structural data to construct a model of the complete integrin receptor in complex with talin F2-F3 domain. It has been shown that the interactions of integrins with their lipid environment are crucial for their function but details of the integrin/lipid interactions remain elusive...
July 27, 2016: Journal of Membrane Biology
https://www.readbyqxmd.com/read/27459426/conformational-changes-in-the-epidermal-growth-factor-receptor-role-of-the-transmembrane-domain-investigated-by-coarse-grained-metadynamics-free-energy-calculations
#11
Mickaël Lelimousin, Vittorio Limongelli, Mark S P Sansom
The epidermal growth factor receptor (EGFR) is a dimeric membrane protein that regulates key aspects of cellular function. Activation of the EGFR is linked to changes in the conformation of the transmembrane (TM) domain, brought about by changes in interactions of the TM helices of the membrane lipid bilayer. Using an advanced computational approach that combines Coarse-Grained molecular dynamics and well-tempered MetaDynamics (CG-MetaD), we characterize the large-scale motions of the TM helices, simulating multiple association and dissociation events between the helices in membrane, thus leading to a free energy landscape of the dimerization process...
August 24, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27459095/multiscale-simulations-suggest-a-mechanism-for-the-association-of-the-dok7-ph-domain-with-pip-containing-membranes
#12
Amanda Buyan, Antreas C Kalli, Mark S P Sansom
Dok7 is a peripheral membrane protein that is associated with the MuSK receptor tyrosine kinase. Formation of the Dok7/MuSK/membrane complex is required for the activation of MuSK. This is a key step in the complex exchange of signals between neuron and muscle, which lead to neuromuscular junction formation, dysfunction of which is associated with congenital myasthenic syndromes. The Dok7 structure consists of a Pleckstrin Homology (PH) domain and a Phosphotyrosine Binding (PTB) domain. The mechanism of the Dok7 association with the membrane remains largely unknown...
July 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/27437577/structural-basis-of-smoothened-regulation-by-its-extracellular-domains
#13
Eamon F X Byrne, Ria Sircar, Paul S Miller, George Hedger, Giovanni Luchetti, Sigrid Nachtergaele, Mark D Tully, Laurel Mydock-McGrane, Douglas F Covey, Robert P Rambo, Mark S P Sansom, Simon Newstead, Rajat Rohatgi, Christian Siebold
Developmental signals of the Hedgehog (Hh) and Wnt families are transduced across the membrane by Frizzledclass G-protein-coupled receptors (GPCRs) composed of both a heptahelical transmembrane domain (TMD) and an extracellular cysteine-rich domain (CRD). How the large extracellular domains of GPCRs regulate signalling by the TMD is unknown. We present crystal structures of the Hh signal transducer and oncoprotein Smoothened, a GPCR that contains two distinct ligand-binding sites: one in its TMD and one in the CRD...
July 28, 2016: Nature
https://www.readbyqxmd.com/read/27427480/interactions-of-pleckstrin-homology-domains-with-membranes-adding-back-the-bilayer-via-high-throughput-molecular-dynamics
#14
Eiji Yamamoto, Antreas C Kalli, Kenji Yasuoka, Mark S P Sansom
A molecular simulation pipeline for determining the mode of interaction of pleckstrin homology (PH) domains with phosphatidylinositol phosphate (PIP)-containing lipid bilayers is presented. We evaluate our methodology for the GRP1 PH domain via comparison with structural and biophysical data. Coarse-grained simulations yield a 2D density landscape for PH/membrane interactions alongside residue contact profiles. Predictions of the membrane localization and interactions of 13 PH domains reveal canonical, non-canonical, and dual PIP-binding sites on the proteins...
August 2, 2016: Structure
https://www.readbyqxmd.com/read/27357679/sleeping-beauty-screen-reveals-pparg-activation-in-metastatic-prostate-cancer
#15
Imran Ahmad, Ernest Mui, Laura Galbraith, Rachana Patel, Ee Hong Tan, Mark Salji, Alistair G Rust, Peter Repiscak, Ann Hedley, Elke Markert, Carolyn Loveridge, Louise van der Weyden, Joanne Edwards, Owen J Sansom, David J Adams, Hing Y Leung
Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]...
July 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27341016/molecular-dynamics-simulations-of-membrane-proteins-and-their-interactions-from-nanoscale-to-mesoscale
#16
Matthieu Chavent, Anna L Duncan, Mark Sp Sansom
Molecular dynamics simulations provide a computational tool to probe membrane proteins and systems at length scales ranging from nanometers to close to a micrometer, and on microsecond timescales. All atom and coarse-grained simulations may be used to explore in detail the interactions of membrane proteins and specific lipids, yielding predictions of lipid binding sites in good agreement with available structural data. Building on the success of protein-lipid interaction simulations, larger scale simulations reveal crowding and clustering of proteins, resulting in slow and anomalous diffusional dynamics, within realistic models of cell membranes...
June 21, 2016: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/27222476/cxcr2-and-cxcl4-regulate-survival-and-self-renewal-of-hematopoietic-stem-progenitor-cells
#17
Amy Sinclair, Laura Park, Mansi Shah, Mark Drotar, Simon Calaminus, Lisa E M Hopcroft, Ross Kinstrie, Amelie V Guitart, Karen Dunn, Sheela A Abraham, Owen Sansom, Alison M Michie, Laura Machesky, Kamil R Kranc, Gerard J Graham, Francesca Pellicano, Tessa L Holyoake
The regulation of hematopoietic stem cell (HSC) survival and self-renewal within the bone marrow (BM) niche is not well understood. We therefore investigated global transcriptomic profiling of normal human HSC/hematopoietic progenitor cells [HPCs], revealing that several chemokine ligands (CXCL1-4, CXCL6, CXCL10, CXCL11, and CXCL13) were upregulated in human quiescent CD34(+)Hoescht(-)Pyronin Y(-) and primitive CD34(+)38(-), as compared with proliferating CD34(+)Hoechst(+)Pyronin Y(+) and CD34(+)38(+) stem/progenitor cells...
July 21, 2016: Blood
https://www.readbyqxmd.com/read/27206747/development-of-a-duplex-ultrasound-simulator-and-preliminary-validation-of-velocity-measurements-in-carotid-artery-models
#18
R Eugene Zierler, Daniel F Leotta, Kurt Sansom, Alberto Aliseda, Mark D Anderson, Florence H Sheehan
OBJECTIVE: Duplex ultrasound scanning with B-mode imaging and both color Doppler and Doppler spectral waveforms is relied upon for diagnosis of vascular pathology and selection of patients for further evaluation and treatment. In most duplex ultrasound applications, classification of disease severity is based primarily on alterations in blood flow velocities, particularly the peak systolic velocity (PSV) obtained from Doppler spectral waveforms. We developed a duplex ultrasound simulator for training and assessment of scanning skills...
July 2016: Vascular and Endovascular Surgery
https://www.readbyqxmd.com/read/27109430/free-energy-landscape-of-lipid-interactions-with-regulatory-binding-sites-on-the-transmembrane-domain-of-the-egf-receptor
#19
George Hedger, David Shorthouse, Heidi Koldsø, Mark S P Sansom
Lipid molecules can bind to specific sites on integral membrane proteins, modulating their structure and function. We have undertaken coarse-grained simulations to calculate free energy profiles for glycolipids and phospholipids interacting with modulatory sites on the transmembrane helix dimer of the EGF receptor within a lipid bilayer environment. We identify lipid interaction sites at each end of the transmembrane domain and compute interaction free energy profiles for lipids with these sites. Interaction free energies ranged from ca...
August 25, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27091502/super-complexes-of-adhesion-gpcrs-and-neural-guidance-receptors
#20
Verity A Jackson, Shahid Mehmood, Matthieu Chavent, Pietro Roversi, Maria Carrasquero, Daniel Del Toro, Goenuel Seyit-Bremer, Fanomezana M Ranaivoson, Davide Comoletti, Mark S P Sansom, Carol V Robinson, Rüdiger Klein, Elena Seiradake
Latrophilin adhesion-GPCRs (Lphn1-3 or ADGRL1-3) and Unc5 cell guidance receptors (Unc5A-D) interact with FLRT proteins (FLRT1-3), thereby promoting cell adhesion and repulsion, respectively. How the three proteins interact and function simultaneously is poorly understood. We show that Unc5D interacts with FLRT2 in cis, controlling cell adhesion in response to externally presented Lphn3. The ectodomains of the three proteins bind cooperatively. Crystal structures of the ternary complex formed by the extracellular domains reveal that Lphn3 dimerizes when bound to FLRT2:Unc5, resulting in a stoichiometry of 1:1:2 (FLRT2:Unc5D:Lphn3)...
2016: Nature Communications
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