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The dynamic response of a fungal lipase in the presence of charged surfactants

COLLOIDS AND SURFACES B-BIOINTERFACES 2002年第1-2期26卷 84-101页

作者： Peters, GH Tech Univ Denmark Dept Chem Ctr Biomembrane Phys MEMPHYS DK-2800 Lyngby Denmark

Lipases are efficient catalysts for lipolytic reactions and require a lipid interface for optimal activity. To study the effect of small charged lipid aggregates on the behavior of these enzymes, we have performed molecular dynamics simulations on five different systems. The simulations carried out in periodic boundary conditions and including explicit water molecules were performed for 2 ns. The lipids were either fatty acid molecules or amines to present negatively or positively charged species. The lipids were partially (i.e. mixture of charged and uncharged lipids) or fully charged. The lipids are randomly placed closely to the active site lid. Our results indicate that in all simulations different lipids do not affect the overall protein structure. However, conformational changes and internal motions in the protein are significantly influenced by the presence of the lipid molecules. In an aqueous environment, protein motions are mainly concentrated in three segments, which are Lys53-Asn63, Ser83-Asn86 and the C-terminus. The former region is structurally conserved in the lipase family and has been proposed to be involved in the activation of lipases. Interestingly, in the presence of the lipid molecules these fluctuations are suppressed, which is partly due to the interaction of the C-terminus with the lipid molecules. This may suggest that the C-terminus (which is not conserved in the lipase family) may have an important role in recognizing and binding to different lipid surfaces. In the presence of lipid aggregates, fluctuations are observed in the loops Va197-Lys106, Arg202-Gly214 and Trp223-Thr252. In particular, the flexibility of the loop Va197-Lys106 may have fundamental implications for the activation of lipases. This region has been suggested as a possible 'entering gate' for substrate molecules to the binding cleft. (C) 2002 Elsevier Science B.V. All rights reserved.

关键词： lipid patch molecular dynamics simulations molecular modeling protein flexibility Rhizomucor miehei lipase structure-function relationships

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Glycosylation of Thermomyces lanuginosa lipase enhances surface binding towards phospholipids, but does not significantly influence the catalytic activity

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COLLOIDS AND SURFACES B-BIOINTERFACES 2002年第1-2期26卷 125-134页

作者： Peters, GH Svendsen, A Langberg, H Vind, J Patkar, SA Kinnunen, PKJ Tech Univ Denmark Dept Chem Ctr Biomembraen Phys MEMPHYS DK-2800 Lyngby Denmark Novozymes AS DK-2880 Bagsvaerd Denmark Univ Helsinki Inst Biomed Dept Med Chem Helsinki Finland

Binding properties of the native Thermomyces lanuginosa lipase (Tll), the inactive mutant of Tll (S146A;active Ser146 mutated to Ala), and the non-glycosylated mutant of Tll (N33Q) Were determined using fluorescence spectroscopy. Tll, S146A mutant and N33Q mutant show significant different binding behavior to phosphatidylcholine (PC) and phosphatidylglycerol (PG) liposomes. Generally, weaker association of lipase molecules is observed to PC liposomes than to PG liposomes. Strong lipase-lipid interactions are observed for the S146A mutant, which is less pronounced for Tll and the N33Q variant. Addition of fatty acid to PG liposomes reduces significantly the binding affinity of the lipases. This effect is less pronounced in fatty acid/PC liposomes. Although the catalytic activity of the N33Q mutant is comparable to Tll, the non-glycosylated variant shows generally lower binding affinity to PC or PG matrix than Tll. Addition of the substrate analog benzene boronic acid (BBA) increases the binding affinity of the S146A and N33Q mutants, while only small changes are observed for Tll suggesting that the dynamics of the active-site lid influences the binding affinity and that the flexibility of the loop region 33-48 might contribute to the activation of the lipase. (C) 2002 Elsevier Science B.V. All rights reserved.

关键词： energy transfer fluorescence spectroscopy interfacial surface quality monolayers structure-function relationships

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The dynamic response of a fungal lipase in the presence of charged surfactants

The dynamic response of a fungal lipase in the presence of c...

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European Meeting on Lipid and Lipase Interaction

作者： Peters, GH Tech Univ Denmark Dept Chem Ctr Biomembrane Phys MEMPHYS DK-2800 Lyngby Denmark

关键词： lipid patch molecular dynamics simulations molecular modeling protein flexibility Rhizomucor miehei lipase structure-function relationships

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Molecular design versus empirical discovery in peptide-based vaccines. Coming to terms with fuzzy recognition sites and ill-defined structure-function relationships in immunology

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VACCINE 1999年第3-4期18卷 216-221页

作者： van Regenmortel, MHV CNRS Inst Biol Mol & Cellulaire F-67084 Strasbourg France

In view of our increased understanding of the molecular basis of immunological recognition, it is commonly believed that it should be possible to apply molecular design strategies to the development of peptide-based vaccines. The stated aim is to transform the development of a Vaccine from a trial and error empirical operation into a so-called rational, structure-based process. In the present review, it is argued that it is misleading to oppose rational and empirical approaches in vaccine research since both are needed in the practice of experimental science. Many reasons are given for the view-that the molecular design of synthetic vaccines is not a realistic scientific enterprise. The capacity of a peptide to induce a protective immune response depends on many extrinsic factors and regulatory mechanisms of the recipient host which are not amenable to molecular design of the peptide immunogen. It seems safe to predict that the development of peptide-based vaccines will continue to be driven by empirical discovery rather than by so-called rational design, (C) 1999 Elsevier Science Ltd. AU rights reserved.

关键词： molecular design peptide-based vaccines structure-function relationships

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Glycosylation of Thermomyces lanuginosa lipase enhances surface binding towards phospholipids, but does not significantly influence the catalytic activity

Glycosylation of <i>Thermomyces lanuginosa</i> lipase enhanc...

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European Meeting on Lipid and Lipase Interaction

关键词： energy transfer fluorescence spectroscopy interfacial surface quality monolayers structure-function relationships

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Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception

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Reviews in Endocrine and Metabolic Disorders 2002年第3期3卷 211-224页

作者： Stanczyk, Frank Z. Department of Obstetrics University of Southern California Keck School of Medicine Los Angeles CA 90033 United States

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structure-function studies of an IGF-I analogue that can be chemically cleaved to a two-chain mini-IGF-I

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PROTEIN ENGINEERING 2001年第1期14卷 61-65页

作者： Geddes, S Holst, P Grotzinger, J Gill, R Nugent, P De Meyts, P Wollmer, A Wood, S Pitts, J Univ London Birkbeck Coll Sch Crystallog London WC1 7HX England Hagedorn Res Inst DK-2820 Gentofte Denmark Rhein Westfal TH Aachen Inst Biochim D-52057 Aachen Germany Univ Southampton Sch Biol Sci Dept Biochem Southampton SO16 7PX Hants England

The structure and biological activities of two disulphide isomers of a C-region deletion mutant of insulin-like growth factor-I (IGF-I) which has an Asn-Gly link engineered at the junction of the A- and B-regions were studied before and after chemical cleavage. Circular dichroism (CD) spectra and binding affinity to IGF binding protein 3 (IGFBP3) indicated that the treatment with hydroxylamine did not disrupt the overall tertiary fold of the hormones. Cleavage restored some binding affinity for the IGF-I receptor in both isomers and weakly restored the ability to stimulate incorporation of tritiated thymidine into DNA in NIH 3T3 fibroblasts transfected with the human IGF-I receptor. Cleavage also restored metabolic capacity, as measured by the ability of the isomers to promote lipogenesis in isolated rat adipocytes through the insulin receptor. These results are consistent with the theory that binding of IGF-I to the IGF-I receptor requires a conformational change similar to that involved in insulin binding the insulin receptor. The weak affinity for the IGF-I receptor after cleavage is consistent with the belief that residues in the C-region interact with the FGF-I receptor. This structural difference between insulin and IGF-I gives each a higher binding affinity for its own receptor.

关键词： insulin insulin-like growth factor-I receptor binding structure-function relationships

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structure-function relationship of three triple-helical nucleic acids

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JOURNAL OF BIOMOLECULAR structure & DYNAMICS 2001年第5期18卷 671-676页

作者： Giacometti, A Univ Ca Foscari Venice Fac Sci MMFFNN Dept Environm Sci I-30123 Venice Italy

The nucleic acid triplexes poly d(T).poly d(A).poly d(T), poly (U).poly (A).poly (U), and poly (I).poly (A).poly (I) display a sort of continuity between each other. However, their morphologies present their own individuality which, considering those of their parent duplexes, are quite unexpected. This comparison helps to understand tripler structure-function relationship. While helical parameters are functions of the sugar pucker, low values of WC and Hoogsteen base-pair propellers is commonplace for triplexes and the Hoogsteen base-pair geometry monitors the effects of the interstrand phosphates charge-charge repulsion.

关键词： Nucleic Acid Conformation Polynucleotides Poly A Poly T poly(dA) Poly I 核酸构象聚核苷酸类 polyadenylic acid Nucleic Acid Conformation Nucleotides polyuridylic acid structure-function relationships polythymidylic acid Nucleic acids polyinosinic acid Polynucleotides

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Multimodal characterisation of cortical areas by multivariate analyses of receptor binding and connectivity data

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ANATOMY AND EMBRYOLOGY 2001年第4期204卷 333-350页

作者： Kötter, R Stephan, KE Palomero-Gallagher, N Geyer, S Schleicher, A Zilles, K Univ Dusseldorf C&O Vogt Inst Hirnforsch D-40225 Dusseldorf Germany Univ Dusseldorf Inst Morphol Endocrinol & Histochem D-40225 Dusseldorf Germany Forschungszentrum Julich Inst Med D-52425 Julich Germany Univ Dusseldorf Inst Neuroanat D-40225 Dusseldorf Germany Newcastle Univ Dept Psychol Newcastle Upon Tyne NE1 7RU Tyne & Wear England

Cortical areas are regarded as fundamental structural and functional units within the information processing networks of the brain. Their properties have been described extensively by cyto-, myelo- and chemoarchitectonics, cortical and extracortical connectivity patterns, receptive field mapping, activation properties, lesion effects, and other structural and functional characteristics. Systematic integrative approaches aiming at multimodal characterisations of cortical areas or at the delineation of global features of the cortical network, however, are still scarce and usually limited to a single data modality, such as cytoarchitectonical or tract tracing data. Here we describe a methodological framework for the systematic evaluation, comparison and integration of different data modalities from the brain and demonstrate its practical application and significance in the analysis of receptor binding and connectivity data within the motor and visual cortices of macaque monkeys. The framework builds on algorithmic methods to convert data between different cortical parcellation schemes, as well as on statistical techniques for the exploration of multivariate data sets comprising data of different types and scales. Thereby, we establish a relationship between intrinsic area properties as expressed by quantitative receptor binding, and extrinsic inter-area communication, which relies on anatomical connectivity. Our analyses provide preliminary evidence for a good correspondence of these two data types in the motor cortex, and their partial discrepancy in the visual cortex, raising hypotheses about the different organisational aspects highlighted by receptors and connectivity. The methodological framework presented here is flexible enough to accommodate a wide range of further data modalities, and is specific enough to permit novel insights and predictions concerning brain organisation. Thus, this approach promises to be very useful in the endeavour to characterise multimo

关键词： multivariate statistics structure-function relationships visual cortex motor cortex primate

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Thyrotropin receptor mutations as a tool to understand thyrotropin receptor action

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JOURNAL OF MOLECULAR MEDICINE-JMM 2001年第12期79卷 707-721页

作者： Wonerow, P Neumann, S Gudermann, T Paschke, R Univ Leipzig Med Klin D-04103 Leipzig Germany Univ Marburg Fachbereich Humanmed Inst Pharmakol & Toxikol D-35033 Marburg Germany

A large number of mutations have been identified in the thyrotropin (TSH) receptor (TSHR) gene causing human diseases. Toxic thyroid nodules are frequently associated with somatic constitutively activating TSHR mutations. Autosomal dominant nonautoimmune hyperthyroidism is caused by activating TSHR germline mutations. Inactivating germline mutations cause TSH unresponsivness. Discovery of the different TSHR mutations in various regions of the receptor molecule has led to the identification of important domains for intramolecular TSHR signal transduction. However, despite the functional characterization of the naturally occurring mutations the precise molecular mechanisms of receptor activation including the processes of hormone binding, intramolecular signaling between the different TSHR domains and of G protein coupling are not completely understood. This review discusses the importance of the various receptor domains for TSHR activation identified on the basis of the naturally occurring gain or loss of function mutations and in vitro investigations performed with site-directed mutagenesis, synthetic peptides, or antibodies. Several in vitro studies have provided new insights into structure-function relationships by site-directed mutagenesis in combination with molecular modeling. These in vitro investigations have often been guided by naturally occurring mutations and have provided new insights into intramolecular changes during receptor activation. This has led to progress in understanding the mechanism of TSHR activation.

关键词： thyrotropin receptor mutations site-directed mutagenesis structure-function relationships

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