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Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors UNIQUE ROLE OF HALOGEN BONDING REVEALED

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JOURNAL OF BIOLOGICAL CHEMISTRY 2012年第6期287卷 4248-4259页

作者： Rohde, Line Aagot Hede Ahring, Philip Kiaer Jensen, Marianne Lerbech Nielsen, Elsebet Ostergaard Peters, Dan Helgstrand, Charlotte Krintel, Christian Harpsoe, Kasper Gajhede, Michael Kastrup, Jette Sandholm Balle, Thomas Univ Copenhagen Dept Med Chem Fac Pharmaceut Sci DK-2100 Copenhagen Denmark NeuroSearch AS DK-2750 Ballerup Denmark

The alpha 4 beta 2 subtype of the nicotinic acetylcholine receptor has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of alpha 4 beta 2 agonists is lacking. Using binding experiments, electrophysiology and x-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at alpha 4 beta 2 and the acetylcholine-binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for alpha 4 beta 2 receptors. Crystal structures of five agonists with efficacies at alpha 4 beta 2 from 21-76% were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead, the efficacy of a compound appears tightly coupled to its ability to form a strong intersubunit bridge linking the primary and complementary binding interfaces. For the tested agonists, a specific halogen bond was observed to play a large role in establishing such strong intersubunit anchoring.

关键词： Agonist Nicotinic Acetylcholine Drug Liberation structure-function relationships Smoking Cessation Neurodegenerative Diseases halogens Nicotinic Receptors

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Streamlined access to conjugation-ready glycans by automated synthesis

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CHEMICAL SCIENCE 2012年第5期3卷 1617-1622页

作者： Kroeck, Lenz Esposito, Davide Castagner, Bastien Wang, Cheng-Chung Bindschaedler, Pascal Seeberger, Peter H. Max Planck Inst Colloids & Interfaces Dept Biomol Syst D-14476 Potsdam Germany Free Univ Berlin Inst Chem & Biochem D-14195 Berlin Germany

Understanding the structure-function relationship of carbohydrates in biological systems is a major challenge. Such investigations require fast and reliable access to structurally-defined oligosaccharides. To date, oligosaccharide synthesis has been considered technically difficult and only parts of the synthetic process have been automated using solution and solid-phase techniques. Here, we describe a versatile platform integrating a new synthesis strategy and a fully-automated oligosaccharide synthesizer. Structurally diverse conjugation-ready oligosaccharides can be generated for the creation of glycoconjugates and microarrays. Biologically-significant oligosaccharides of increasing length, structural complexity, and chemical diversity were produced, including glycans found on the surfaces of pathogenic bacteria, and those with integral roles in inflammatory and immune responses.

关键词： Oligosaccharides synthesis Surfaces structure-function relationships Polysaccharides Automation biological organs SYNTHETIC PROCESS Glycoconjugates Carbohydrates Pathogenic bacteria Access

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Category Theory Based Solution for the Building Block Replacement Problem in Materials Design

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ADVANCED ENGINEERING MATERIALS 2012年第9期14卷 810-817页

作者： Giesa, Tristan Spivak, David I. Buehler, Markus J. MIT Dept Civil & Environm Engn Lab Atomist & Mol Mech Cambridge MA 02139 USA MIT Ctr Computat Engn Cambridge MA 02139 USA MIT Dept Math Cambridge MA 02139 USA

An important objective in materials design is to develop a systematic methodology for replacing unavailable or expensive material building blocks by simpler and abundant ones, while maintaining or improving the functionality of the material. The mathematical field of category theory provides a formal specification language which lies at the heart of such a methodology. In this paper, we apply material ologs, category-theoretic descriptions of hierarchical materials, to rigorously define a process by which material building blocks can be replaced by others while maintaining large-scale properties, to the extent possible. We demonstrate the implementation of this approach by using algebraic techniques to predict concrete conditions needed for building block replacement. As an example, we specify structurefunction relationships in two systems: a laminated composite and a structurefunction analogue, a fruit salad. In both systems we illustrate how ologs provide us with a mathematical tool that allows us to replace one building block with others to achieve approximately the same functionality, and how to use them to model and design seemingly distinct physical systems with a consistent mathematical framework.

关键词： category theory materials design Buildings structure-function relationships Materials Building blocks specification description language Fruit salads

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Local Tissue Geometry Determines Contractile Force Generation of Engineered Muscle Networks

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TISSUE ENGINEERING PART A 2012年第9-10期18卷 957-967页

作者： Bian, Weining Juhas, Mark Pfeiler, Terry W. Bursac, Nenad Duke Univ Dept Biomed Engn Durham NC 27708 USA Harvard Univ Brigham & Womens Hosp Sch Med Dept Anesthesia & Med Boston MA 02115 USA Harvard Univ Brigham & Womens Hosp Sch Med Cardiovasc Div Boston MA 02115 USA

The field of skeletal muscle tissue engineering is currently hampered by the lack of methods to form large muscle constructs composed of dense, aligned, and mature myofibers and limited understanding of structure-function relationships in developing muscle tissues. In our previous studies, engineered muscle sheets with elliptical pores ("muscle networks'') were fabricated by casting cells and fibrin gel inside elastomeric tissue molds with staggered hexagonal posts. In these networks, alignment of cells around the elliptical pores followed the local distribution of tissue strains that were generated by cell-mediated compaction of fibrin gel against the hexagonal posts. The goal of this study was to assess how systematic variations in pore elongation affect the morphology and contractile function of muscle networks. We found that in muscle networks with more elongated pores the force production of individual myofibers was not altered, but the myofiber alignment and efficiency of myofiber formation were significantly increased yielding an increase in the total contractile force despite a decrease in the total tissue volume. Beyond a certain pore length, increase in generated contractile force was mainly contributed by more efficient myofiber formation rather than enhanced myofiber alignment. Collectively, these studies show that changes in local tissue geometry can exert both direct structural and indirect myogenic effects on the functional output of engineered muscle. Different hydrogel formulations and pore geometries will be explored in the future to further augment contractile function of engineered muscle networks and promote their use for basic structure-function studies in vitro and, eventually, for efficient muscle repair in vivo.

关键词： muscles structure-function relationships Pore Alignment Skeletal muscle Network

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structure-Activity relationships of α-, β₁-, γ-, and δ-Tomatine and Tomatidine against Human Breast (MDA-MB-231), Gastric (KATO-III), and Prostate (PC3) Cancer Cells

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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2012年第15期60卷 3891-3899页

作者： Choi, Suk Hyun Ahn, Jun-Bae Kozukue, Nobuyuki Kim, Hyun-Jeong Nishitani, Yosuke Zhang, Ling Mizuno, Masashi Levin, Carol E. Friedman, Mendel ARS Western Reg Res Ctr USDA Albany CA 94710 USA Seowon Univ Dept Food Serv Ind Cheongju 361742 South Korea Seowon Univ Bio Organ Mat & Food Ctr Cheongju 361742 South Korea Keimyung Univ Ctr Tradit Microorganism Resources Taegu 704701 South Korea Kobe Univ Org Adv Sci & Technol Team Hlth Biosci Kobe Hyogo 6578501 Japan Kobe Univ Dept Agrobiosci Grad Sch Agr Sci Kobe Hyogo 6578501 Japan

Partial acid hydrolysis of the tetrasaccharide (lycotetraose) side chain of the tomato glycoalkaloid alpha-tomatine resulted in the formation of four products with three, two, one, and zero carbohydrate side chains, which were separated by high-performance liquid chromatography (HPLC) and identified by thin-layer chromatography (TLC) and liquid chromatography ion-trap time-of-flight mass spectrometry (LCMS-IT-TOF). The inhibitory activities in terms of IC50 values (concentration that inhibits 50% of the cells under the test conditions) of the parent compound and the hydrolysates, isolated by preparative HPLC, against normal human liver and lung cells and human breast, gastric, and prostate cancer cells indicate that (a) the removal of sugars significantly reduced the concentration-dependent cell-inhibiting effects of the test compounds, (b) PC3 prostate cancer cells were about 10 times more susceptible to inhibition by alpha-tomatine than the breast and gastric cancer cells or the normal cells, (c) the activity of alpha-tomatine against the prostate cancer cells was 200 times greater than that of the aglycone tomatidine, and (d) the activity increased as the number of sugars on the aglycone increased, but this was only statistically significant at p < 0.05 for the normal lung He1299 cell line. The effect of the alkaloids on tumor necrosis factor alpha (TNF-alpha) was measured in RAW264.7 macrophage cells. There was a statistically significant negative correlation between the dosage of gamma- and alpha-tomatine and the level of TNF-alpha. alpha-Tomatine was the most effective compound at reducing TNF-alpha. The dietary significance of the results and future research needs are discussed.

关键词： Tomatoes alpha-tomatine hydrolysis TLC mass spectrometry cancer cells inhibition tumor necrosis factor alpha structure-function relationships mechanisms

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Synthetic polyamines as potential amine oxidase inhibitors: a preliminary study

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AMINO ACIDS 2012年第2-3期42卷 913-928页

作者： Bonaiuto, Emanuela Minarini, Anna Tumiatti, Vincenzo Milelli, Andrea Lunelli, Michele Pegoraro, Maurizio Rizzoli, Valeria Di Paolo, Maria Luisa Univ Padua Dept Biol Chem I-35131 Padua Italy Alma Mater Studiorum Univ Bologna Dept Pharmaceut Sci I-40126 Bologna Italy Max Planck Inst Infect Biol Dept Cellular Microbiol D-10117 Berlin Germany San Bortolo Hosp Dept Plast Surg I-36100 Vicenza Italy Consorzio Interuniv Ist Nazl Biostrutture & Biosi I-00136 Rome Italy

In the last few decades, medicinal chemists have carried out extensive research on synthetic polyamines for use as anticancer drugs and multitarget-directed ligands in neurodegenerative diseases. The aim of this study was to evaluate the effect of some synthetic polyamines as inhibitors of two new potential targets, human semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) and monoamine oxidases B (MAO B), enzymes involved in various multi-factorial diseases such as Alzheimer's disease. N,N'-Dibenzyl-dodecane-1,12-diamine (Bis-Bza-Diado), a newly synthesised compound, and ELP 12, a muscarinic cholinergic M-2 receptor antagonist, were found to behave as reversible and mixed non-competitive inhibitors of both amine oxidases (dissociation constants of about 100 mu M). ELP 12 was found to be more selective for SSAO/VAP-1. Combining kinetic and structural approaches, the binding mode of ELP 12 to SSAO/VAP-1 was investigated. ELP 12 may bind at the entrance of the active site channel by ionic interactions with ASP446 and/or ASP180;one end of the polyamine may be accommodated inside the channel, reaching the TPQ cofactor area. The binding of ELP 12 induces rearrangement of the secondary structure of the enzyme and impedes substrate entry and/or product release and catalysis. These structural data reveal that the entrance and the first part of the SSAO/VAP-1 channel may be considered as a new target area, or a "secondary binding site", for modulators of human SSAO/VAP-1 activity. These results indicate ELP 12 and Bis-Bza-Diado as new "skeletons" for the development of novel SSAO/VAP-1 and MAO B inhibitors.

关键词： Synthetic polyamines Semicarbazide-sensitive amine oxidases Monoamine oxidase B Amine oxidase inhibitors structure-function relationships

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Identification of functional elements of the GDP-fucose transporter SLC35C1 using a novel Chinese hamster ovary mutant

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GLYCOBIOLOGY 2012年第7期22卷 897-911页

作者： Zhang, Peiqing Haryadi, Ryan Chan, Kah Fai Teo, Gavin Goh, John Pereira, Natasha Ann Feng, Huatao Song, Zhiwei ASTAR Bioproc Technol Inst Singapore 138668 Singapore Natl Univ Singapore Dept Biochem Singapore 119077 Singapore

The GDP-fucose transporter SLC35C1 critically regulates the fucosylation of glycans. Elucidation of its structure-function relationships remains a challenge due to the lack of an appropriate mutant cell line. Here we report a novel Chinese hamster ovary (CHO) mutant, CHO-gmt5, generated by the zinc-finger nuclease technology, in which the Slc35c1 gene was knocked out from a previously reported CHO mutant that has a dysfunctional CMP-sialic acid transporter (CST) gene (Slc35a1). Consequently, CHO-gmt5 harbors double genetic defects in Slc35a1 and Slc35c1 and produces N-glycans deficient in both sialic acid and fucose. The structure-function relationships of SLC35C1 were studied using CHO-gmt5 cells. In contrast to the CST and UDP-galactose transporter, the C-terminal tail of SLC35C1 is not required for its Golgi localization but is essential for generating glycans that are recognized by a fucose-binding lectin, Aleuria aurantia lectin (AAL), suggesting an important role in the transport activity of SLC35C1. Furthermore, we found that this impact can be independently contributed by a cluster of three lysine residues and a Glu-Met (EM) sequence within the C terminus. We also showed that the conserved glycine residues at positions 180 and 277 of SLC35C1 have significant impacts on AAL binding to CHO-gmt5 cells, suggesting that these conserved glycine residues are required for the transport activity of Slc35 proteins. The absence of sialic acid and fucose on Fc N-glycan has been independently shown to enhance the antibody-dependent cellular cytotoxicity (ADCC) effect. By combining these features into one cell line, we postulate that CHO-gmt5 may represent a more advantageous cell line for the production of recombinant antibodies with enhanced ADCC effect.

关键词： GDP-fucose transporter glycosylation mutant protein fucosylation structure-function relationships zinc-finger nucleases

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Cardiotoxin-I: An Unexpectedly Potent Insulinotropic Agent

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CHEMBIOCHEM 2012年第12期13卷 1805-1812页

作者： Thi Tuyet Nhung Nguyen Folch, Benjamin Letourneau, Myriam Vaudry, David Nam Hai Truong Doucet, Nicolas Chatenet, David Fournier, Alain Univ Quebec INRS Inst Armand Frappier Laval PQ H7V 1B7 Canada Inst Biotechnol Hanoi Vietnam Univ Rouen IFRMP 23 F-76821 Mont St Aignan France Univ Rouen INRS INSERM Lab Int Associe Samuel de Champlain F-76821 Mont St Aignan France

Insulin secretion from pancreatic beta-cells is a complex process, involving the integration and interaction of multiple external and internal stimuli, in which glucose plays a major role. Understanding the physiology leading to insulin release is a crucial step toward the identification of new targets. In this study, we evaluated the presence of insulinotropic metabolites in Naja kaouthia snake venom. Only one fraction, identified as cardiotoxin-I (CTX-I) was able to induce insulin secretion from INS-1E cells without affecting cell viability and integrity, as assessed by MTT and LDH assays. Interestingly, CTX-I was also able to stimulate insulin secretion from INS-1E cells even in the absence of glucose. Although cardiotoxins have been characterized as potent hemolytic agents and vasoconstrictors, CTX-I was unable to induce direct hemolysis of human erythrocytes or to induce potent vasoconstriction. As such, this newly identified insulin-releasing toxin will surely enrich the pool of existing tools to study beta-cell physiology or even open a new therapeutic avenue.

关键词： cardiotoxin-I insulin ion channels peptides structure-function relationships

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functional Determinants of Temperature Adaptation in Enzymes of Cold- versus Warm-Adapted Mussels (Genus Mytilus)

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MOLECULAR BIOLOGY AND EVOLUTION 2012年第10期29卷 3061-3070页

作者： Lockwood, Brent L. Somero, George N. Stanford Univ Hopkins Marine Stn Stanford CA 94305 USA

Temperature is a strong selective force on the evolution of proteins due to its effects on higher orders of protein structure and, thereby, on critical protein functions like ligand binding and catalysis. Comparisons among orthologous proteins from differently thermally adapted species show consistent patterns of adaptive variation in function, but few studies have examined functional adaptation among multiple structural families of proteins. Thus, with our present state of knowledge, it is difficult to predict what fraction of the proteome will exhibit adaptive variation in the face of temperature increases of a few to several degrees Celsius, that is, temperature increases of the magnitude predicted by models of global warming. Here, we compared orthologous enzymes of the warm-adapted Mediterranean mussel Mytilus galloprovincialis and the cold-adapted Mytilus trossulus, a native of the North Pacific Ocean, species whose physiologies exhibit significantly different responses to temperature. We measured the effects of temperature on the kinetics (Michaelis-Menten constant-K-m) of five enzymes that are important for ATP generation and that represent distinct protein structural families. Among phosphoglucomutase (PGM), phosphoglucose isomerase (PGI), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (GTP) (PEPCK), and isocitrate dehydrogenase (NADP) (IDH), only IDH orthologs showed significantly different thermal responses of K-m between the two species. The K-m of isocitrate of M. galloprovincialis-IDH was intrinsically lower and more thermally stable than that of M. trossulus-IDH and thus had higher substrate affinity at high temperatures. Two amino acid substitutions account for the functional differences between IDH orthologs, one of which allows for more hydrogen bonds to form near the mobile region of the active site in M. galloprovincialis-IDH. Taken together, our findings cast light on the targets of adaptive evolution in the context of climate change;on

关键词： adaptation invasive species Michaelis-Menten constants (K-m) Mytilus protein evolution structure-function relationships temperature

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Biological parametric mapping accounting for random regressors with regression calibration and model II regression

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NEUROIMAGE 2012年第3期62卷 1761-1768页

作者： Yang, Xue Lauzon, Carolyn B. Crainiceanu, Ciprian Caffo, Brian Resnick, Susan M. Landman, Bennett A. Vanderbilt Univ Nashville TN 37235 USA NIA NIH Baltimore MD 21224 USA Johns Hopkins Univ Sch Publ Hlth Baltimore MD 21218 USA Johns Hopkins Univ Baltimore MD 21205 USA

Massively univariate regression and inference in the form of statistical parametric mapping have transformed the way in which multi-dimensional imaging data are studied. In functional and structural neuroimaging, the de facto standard "design matrix"-based general linear regression model and its multi-level cousins have enabled investigation of the biological basis of the human brain. With modem study designs, it is possible to acquire multi-modal three-dimensional assessments of the same individuals-e.g., structural, functional and quantitative magnetic resonance imaging, alongside functional and ligand binding maps with positron emission tomography. Largely, current statistical methods in the imaging community assume that the regressors are non-random. For more realistic multi-parametric assessment (e.g., voxel-wise modeling), distributional consideration of all observations is appropriate. Herein, we discuss two unified regression and inference approaches, model II regression and regression calibration, for use in massively univariate inference with imaging data. These methods use the design matrix paradigm and account for both random and non-random imaging regressors. We characterize these methods in simulation and illustrate their use on an empirical dataset. Both methods have been made readily available as a toolbox plug-in for the SPM software. (c) 2012 Elsevier Inc. All rights reserved.

关键词： structure-function relationships Random regressors Regression calibration Model II regression General linear model

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