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Article: Coulomb effects in binding of heme in gas-phase ions of myoglobin.

Mark, Kevin J / Douglas, D J

Rapid communications in mass spectrometry : RCM

2006 Volume 20, Issue 2, Page(s) 111–117

Abstract: Coulomb effects in binding of heme in gas-phase holomyoglobin ions are studied. Positive and negative ions are formed from solution myoglobin with Fe(2+) (ferromyoglobin) and Fe(3+) (ferrimyoglobin). The energy that must be added to the resulting ... ...

Abstract	Coulomb effects in binding of heme in gas-phase holomyoglobin ions are studied. Positive and negative ions are formed from solution myoglobin with Fe(2+) (ferromyoglobin) and Fe(3+) (ferrimyoglobin). The energy that must be added to the resulting holomyoglobin ions to cause heme loss has been measured by triple-quadrupole tandem mass spectrometry. With negative ions, neutral heme is lost regardless of the charge state of Fe in solution. It is likely that the Fe(3+) is reduced to Fe(2+) in the negative electrospray process. With positive ions, predominantly neutral heme loss is observed with ions formed from ferromyoglobin in solution, and positive heme loss with ions formed from ferrimyoglobin in solution. The energies required to induce neutral heme loss are similar for positive and negative ions. The energies required to induce charged heme loss from positive holomyoglobin ions are significantly less. Coulomb repulsion between the charged heme and charged protein appears to lower the barrier for heme loss. These results are consistent with a simple model potential with a long-range Coulomb repulsion and short-range attraction between the heme and protein.
MeSH term(s)	Algorithms ; Binding Sites ; Computer Simulation ; Gases/analysis ; Gases/chemistry ; Heme/analysis ; Heme/chemistry ; Ions ; Models, Chemical ; Myoglobin/analysis ; Myoglobin/chemistry ; Protein Binding ; Spectrometry, Mass, Electrospray Ionization/methods ; Static Electricity
Chemical Substances	Gases ; Ions ; Myoglobin ; Heme (42VZT0U6YR)
Language	English
Publishing date	2006
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	58731-x
ISSN	1097-0231 ; 0951-4198
ISSN (online)	1097-0231
ISSN	0951-4198
DOI	10.1002/rcm.2273
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Article: Quantification of desmosine and isodesmosine using MALDI-ion trap tandem mass spectrometry

Rathod, Pratikkumar / Kaur, Manjeet / Ho, Hsin-Pin / Louis, Marissa E / Dhital, Basant / Durlik, Philip / Boutis, Gregory S / Mark, Kevin J / Lee, Jong I / Chang, Emmanuel J

Analytical and bioanalytical chemistry. 2018 Oct., v. 410, no. 26

2018

Abstract: Desmosine (Des) and isodesmosine (Isodes), cross-linking amino acids in the biomolecule elastin, may be used as biomarkers for various pathological conditions associated with elastin degradation. The current study presents a novel approach to quantify ... ...

Abstract	Desmosine (Des) and isodesmosine (Isodes), cross-linking amino acids in the biomolecule elastin, may be used as biomarkers for various pathological conditions associated with elastin degradation. The current study presents a novel approach to quantify Des and Isodes using matrix-assisted laser desorption ionization (MALDI)-tandem mass spectrometry (MS2) in a linear ion trap coupled to a vacuum MALDI source. MALDI-MS2 analyses of Des and Isodes are performed using stable-isotope-labeled desmosine d4 (labeled-Des) as an internal standard in different biological fluids, such as urine and serum. The method demonstrated linearity over two orders of magnitude with a detection limit of 0.02 ng/μL in both urine and serum without enrichment prior to mass spectrometry, and relative standard deviation of < 5%. The method is used to evaluate the time-dependent degradation of Des upon UV irradiation (254 nm) and found to be consistent with quantification by 1H NMR. This is the first characterized MALDI-MS2 method for quantification of Des and Isodes and illustrates the potential of MALDI-ion trap MS2 for effective quantification of biomolecules. The reported method represents improvement over current liquid chromatography-based methods with respect to analysis time and solvent consumption, while maintaining similar analytical characteristics. Graphical abstract ᅟ
Keywords	amino acids ; biomarkers ; blood serum ; crosslinking ; desorption ; elastin ; ionization ; liquid chromatography ; nuclear magnetic resonance spectroscopy ; solvents ; statistical analysis ; tandem mass spectrometry ; ultraviolet radiation ; urine
Language	English
Dates of publication	2018-10
Size	p. 6881-6889.
Publishing place	Springer Berlin Heidelberg
Document type	Article
ISSN	1618-2642
DOI	10.1007/s00216-018-1288-z
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Article ; Online: Quantification of desmosine and isodesmosine using MALDI-ion trap tandem mass spectrometry.

Rathod, Pratikkumar / Kaur, Manjeet / Ho, Hsin-Pin / Louis, Marissa E / Dhital, Basant / Durlik, Philip / Boutis, Gregory S / Mark, Kevin J / Lee, Jong I / Chang, Emmanuel J

Analytical and bioanalytical chemistry

2018 Volume 410, Issue 26, Page(s) 6881–6889

Abstract	Desmosine (Des) and isodesmosine (Isodes), cross-linking amino acids in the biomolecule elastin, may be used as biomarkers for various pathological conditions associated with elastin degradation. The current study presents a novel approach to quantify Des and Isodes using matrix-assisted laser desorption ionization (MALDI)-tandem mass spectrometry (MS
MeSH term(s)	Desmosine/analysis ; Desmosine/blood ; Desmosine/chemistry ; Desmosine/urine ; Humans ; Limit of Detection ; Reference Standards ; Reproducibility of Results ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods ; Tandem Mass Spectrometry/methods
Chemical Substances	Desmosine (11003-57-9)
Language	English
Publishing date	2018-07-31
Publishing country	Germany
Document type	Journal Article
ZDB-ID	201093-8
ISSN	1618-2650 ; 0016-1152 ; 0372-7920
ISSN (online)	1618-2650
ISSN	0016-1152 ; 0372-7920
DOI	10.1007/s00216-018-1288-z
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Article ; Online: Initial insights into structure-activity relationships of avian defensins.

Derache, Chrystelle / Meudal, Hervé / Aucagne, Vincent / Mark, Kevin J / Cadène, Martine / Delmas, Agnès F / Lalmanach, Anne-Christine / Landon, Céline

The Journal of biological chemistry

2011 Volume 287, Issue 10, Page(s) 7746–7755

Abstract: Numerous β-defensins have been identified in birds, and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism ... ...

Abstract	Numerous β-defensins have been identified in birds, and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian β-defensins, and this study was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both L- and D-proteins clearly indicates that there is no chiral partner. Therefore, the bacterial membrane is in all likelihood the primary target. Moreover, this work indicates that the three-dimensional fold is required for an optimal antimicrobial activity, in particular for gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural three-stranded antiparallel β-sheet characteristic of β-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of the avian β-defensin family was analyzed. Well conserved residues were highlighted, and the potential strategic role of the lysine 31 residue of AvBD2 was emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity.
MeSH term(s)	Animals ; Avian Proteins/chemistry ; Cell Membrane/chemistry ; Chickens ; Gram-Positive Bacteria/chemistry ; Magnetic Resonance Spectroscopy ; Protein Structure, Secondary ; Structure-Activity Relationship ; beta-Defensins/chemistry
Chemical Substances	Avian Proteins ; beta-Defensins
Language	English
Publishing date	2011-12-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M111.312108
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Article ; Online: Studies on quantitative phosphopeptide analysis by matrix-assisted laser desorption/ionization mass spectrometry without label, chromatography or calibration curves.

Ho, Hsin-Pin / Rathod, Pratikkumar / Louis, Marissa / Tada, Christine K / Rahaman, Sherida / Mark, Kevin J / Leng, Jin / Dana, Dibyendu / Kumar, Sanjai / Lichterfeld, Mathias / Chang, Emmanuel J

Rapid communications in mass spectrometry : RCM

2014 Volume 28, Issue 24, Page(s) 2681–2689

Abstract: Rationale: Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry combined with isotope labeling methods are effective for protein and peptide quantification, but limited in their multiplexing capacity, cost-effectiveness and dynamic ... ...

Abstract	Rationale: Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry combined with isotope labeling methods are effective for protein and peptide quantification, but limited in their multiplexing capacity, cost-effectiveness and dynamic range. This study investigates MALDI-MS-based quantification of peptide phosphorylation without labeling, and aims to overcome the shot-to-shot variability of MALDI using a mathematical transformation and extended data acquisition times. Methods: A linear relationship between the reciprocal of phosphopeptide mole fraction and the reciprocal of phosphorylated-to-unphosphorylated signal ratio is derived, and evaluated experimentally using three separate phosphopeptide systems containing phosphorylated serine, threonine and tyrosine residues: mixtures of phosphopeptide and its des-phospho-analog with known stoichiometry measured by vacuum MALDI-linear ion trap mass spectrometry and fit to the linear model. The model is validated for quantifying in vitro phosphorylation assays with inhibition studies on Cdk2/cyclinA. Results: Dynamic range of picomoles to femtomoles, good accuracy (deviations of 1.5-3.0% from expected values) and reproducibility (relative standard deviation (RSD) = 4.3-6.3%) are achieved. Inhibition of cyclin-dependent kinase phosphorylation by the classical inhibitors olomoucine and r-roscovitine was evaluated and IC50 values found to be in agreement with reported literature values. These results, achieved with single-point calibration, without isotope or chromatography, compare favorably to those arrived at using isotope dilution (p > 0.5 for accuracy). Conclusions: The mathematical relationship derived here can be applied to a method that we term Double Reciprocal Isotope-free Phosphopeptide Quantification (DRIP-Q), as a strategy for quantification of in vitro phosphorylation assays, the first MALDI-based, isotope- and calibration curve-free method of its type. These results also pave the way for further systematic studies investigating the effect of peptide composition and experimental conditions on quantitative, label-free MALDI.
MeSH term(s)	Amino Acid Sequence ; Calibration ; Chromatography, High Pressure Liquid/methods ; Cyclin A/antagonists & inhibitors ; Cyclin A/metabolism ; Cyclin-Dependent Kinase 2/antagonists & inhibitors ; Cyclin-Dependent Kinase 2/metabolism ; Linear Models ; Molecular Sequence Data ; Phosphopeptides/analysis ; Phosphopeptides/chemistry ; Phosphopeptides/metabolism ; Phosphorylation ; Reproducibility of Results ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
Chemical Substances	Cyclin A ; Phosphopeptides ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22)
Language	English
Publishing date	2014-12-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	58731-x
ISSN	1097-0231 ; 0951-4198
ISSN (online)	1097-0231
ISSN	0951-4198
DOI	10.1002/rcm.7063
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Article ; Online: Development of cell-active non-peptidyl inhibitors of cysteine cathepsins.

Dana, Dibyendu / Davalos, Anibal R / De, Shatarupa / Rathod, Pratikkumar / Gamage, Ranjith K / Huestis, Juliana / Afzal, Nisar / Zavlanov, Yuriy / Paroly, Suneeta S / Rotenberg, Susan A / Subramaniam, Gopal / Mark, Kevin J / Chang, Emmanuel J / Kumar, Sanjai

Bioorganic & medicinal chemistry

2013 Volume 21, Issue 11, Page(s) 2975–2987

Abstract: Cysteine cathepsins are an important class of enzymes that coordinate a variety of important cellular processes, and are implicated in various types of human diseases. However, small molecule inhibitors that are cell-permeable and non-peptidyl in nature ... ...

Abstract	Cysteine cathepsins are an important class of enzymes that coordinate a variety of important cellular processes, and are implicated in various types of human diseases. However, small molecule inhibitors that are cell-permeable and non-peptidyl in nature are scarcely available. Herein the synthesis and development of sulfonyloxiranes as covalent inhibitors of cysteine cathepsins are reported. From a library of compounds, compound 5 is identified as a selective inhibitor of cysteine cathepsins. Live cell imaging and immunocytochemistry of metastatic human breast carcinoma MDA-MB-231 cells document the efficacy of compound 5 in inhibiting cysteine cathepsin activity in living cells. A cell-motility assay demonstrates that compound 5 is effective in mitigating the cell-migratory potential of highly metastatic breast carcinoma MDA-MB-231 cells.
MeSH term(s)	Cathepsins/antagonists & inhibitors ; Cathepsins/chemistry ; Cell Line, Tumor ; Cell Movement/drug effects ; Cysteine/chemistry ; Cysteine Proteinase Inhibitors/chemical synthesis ; Cysteine Proteinase Inhibitors/chemistry ; Cysteine Proteinase Inhibitors/pharmacology ; Epoxy Compounds/chemical synthesis ; Epoxy Compounds/chemistry ; Epoxy Compounds/pharmacology ; Humans ; Kinetics ; Molecular Docking Simulation ; Structure-Activity Relationship ; Sulfones/chemical synthesis ; Sulfones/chemistry ; Sulfones/pharmacology ; Thermodynamics
Chemical Substances	Cysteine Proteinase Inhibitors ; Epoxy Compounds ; Sulfones ; Cathepsins (EC 3.4.-) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2013-06-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2013.03.062
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Article: Development of cell-active non-peptidyl inhibitors of cysteine cathepsins

Bioorganic & medicinal chemistry. 2013 June 1, v. 21, no. 11

2013

Abstract	Cysteine cathepsins are an important class of enzymes that coordinate a variety of important cellular processes, and are implicated in various types of human diseases. However, small molecule inhibitors that are cell-permeable and non-peptidyl in nature are scarcely available. Herein the synthesis and development of sulfonyloxiranes as covalent inhibitors of cysteine cathepsins are reported. From a library of compounds, compound 5 is identified as a selective inhibitor of cysteine cathepsins. Live cell imaging and immunocytochemistry of metastatic human breast carcinoma MDA-MB-231 cells document the efficacy of compound 5 in inhibiting cysteine cathepsin activity in living cells. A cell-motility assay demonstrates that compound 5 is effective in mitigating the cell-migratory potential of highly metastatic breast carcinoma MDA-MB-231 cells.
Keywords	breast neoplasms ; cathepsins ; cell movement ; chemistry ; cysteine ; human diseases ; humans ; image analysis ; immunocytochemistry ; metastasis
Language	English
Dates of publication	2013-0601
Size	p. 2975-2987.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2013.03.062
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Article ; Online: Design, synthesis, and evaluation of 2-(arylsulfonyl)oxiranes as cell-permeable covalent inhibitors of protein tyrosine phosphatases.

Dana, Dibyendu / Das, Tirtha K / Kumar, Ish / Davalos, Anibal R / Mark, Kevin J / Ramai, Daryl / Chang, Emmanuel J / Talele, Tanaji T / Kumar, Sanjai

Chemical biology & drug design

2012 Volume 80, Issue 4, Page(s) 489–499

Abstract: A structure-based design approach has been applied to develop 2-(arylsulfonyl)oxiranes as potential covalent inhibitors of protein tyrosine phosphatases. A detailed kinetic analysis of inactivation by these covalent inhibitors reveals that this class of ... ...

Abstract	A structure-based design approach has been applied to develop 2-(arylsulfonyl)oxiranes as potential covalent inhibitors of protein tyrosine phosphatases. A detailed kinetic analysis of inactivation by these covalent inhibitors reveals that this class of compounds inhibits a panel of protein tyrosine phosphatases in a time- and dose-dependent manner, consistent with the covalent modification of the enzyme active site. An inactivation experiment in the presence of sodium arsenate, a known competitive inhibitor of protein tyrosine phosphatase, indicated that these inhibitors were active site bound. This finding is consistent with the mass spectrometric analysis of the covalently modified protein tyrosine phosphatase enzyme. Additional experiments indicated that these compounds remained inert toward other classes of arylphosphate-hydrolyzing enzymes, and alkaline and acid phosphatases. Cell-based experiments with human A549 lung cancer cell lines indicated that 2-(phenylsulfonyl)oxirane (1) caused an increase in intracellular pTyr levels in a dose-dependent manner thereby suggesting its cell-permeable nature. Taken together, the newly identified 2-(arylsulfonyl)oxiranyl moiety could serve as a novel chemotype for the development of activity-based probes and therapeutic agents against protein tyrosine phosphatase superfamily of enzymes.
MeSH term(s)	Binding Sites ; Catalytic Domain ; Cell Line, Tumor ; Drug Design ; Epoxy Compounds/chemical synthesis ; Epoxy Compounds/chemistry ; Epoxy Compounds/pharmacokinetics ; Epoxy Compounds/pharmacology ; Humans ; Models, Molecular ; Protein Tyrosine Phosphatases/antagonists & inhibitors ; Protein Tyrosine Phosphatases/chemistry ; Protein Tyrosine Phosphatases/metabolism ; Structure-Activity Relationship
Chemical Substances	Epoxy Compounds ; Protein Tyrosine Phosphatases (EC 3.1.3.48)
Language	English
Publishing date	2012-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2216600-2
ISSN	1747-0285 ; 1747-0277
ISSN (online)	1747-0285
ISSN	1747-0277
DOI	10.1111/j.1747-0285.2012.01437.x
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Article: Initial insights into structure-activity relationships of avian defensins

Derache, Chrystelle / Meudal, Hervé / Aucagne, Vincent / Mark, Kevin J. / Cadène, Martine / Delmas, Agnès F. / Lalmanach, Anne-Christine / Landon, Céline

Journal of Biological Chemistry 10 (287), 7746-7755. (2012)

Abstract	Numerous β-defensins have been identified in birds, and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian β-defensins, and this study was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both l- and d-proteins clearly indicates that there is no chiral partner. Therefore, the bacterial membrane is in all likelihood the primary target. Moreover, this work indicates that the three-dimensional fold is required for an optimal antimicrobial activity, in particular for Gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural three-stranded antiparallel β-sheet characteristic of β-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of the avian β-defensin family was analyzed. Well conserved residues were highlighted, and the potential strategic role of the lysine 31 residue of AvBD2 was emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity.
Language	English
Document type	Article
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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Article: Initial insights into structure-activity relationships of avian defensins

Derache, Chrystelle / Meudal, Hervé / Aucagne, Vincent / Mark, Kevin J. / Cadène, Martine / Delmas, Agnès F. / Lalmanach, Anne-Christine / Landon, Céline

Journal of Biological Chemistry 10 (287), 7746-7755. (2012)

Abstract	Numerous β-defensins have been identified in birds, and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian β-defensins, and this study was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both l- and d-proteins clearly indicates that there is no chiral partner. Therefore, the bacterial membrane is in all likelihood the primary target. Moreover, this work indicates that the three-dimensional fold is required for an optimal antimicrobial activity, in particular for Gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural three-stranded antiparallel β-sheet characteristic of β-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of the avian β-defensin family was analyzed. Well conserved residues were highlighted, and the potential strategic role of the lysine 31 residue of AvBD2 was emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity.
Language	English
Document type	Article
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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