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Wen Hwa Lee - One of the best experts on this subject based on the ideXlab platform.
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Structural and Biochemical Characterization of the Human Cyclophilin Family of Peptidyl-Prolyl Isomerases
2016Co-Authors: Tara L Davis, Elan Z Eisenmesser, John R Walker, P J Finerty, Galina Bernstein, F Mackenzie, Wolfram Tempel, Hui Ouyang, Wen Hwa Lee, Sirano Dhe-paganonAbstract:Peptidyl-prolyl isomerases catalyze the conversion between cis and trans isomers of proline. The cyclophilin family of peptidyl-prolyl isomerases is well known for being the target of the immunosuppressive Drug cyclosporin, used to combat organ transplant rejection. There is great interest in both the substrate Specificity of these enzymes and the design of isoform-selective ligands for them. However, the dearth of available data for individual family members inhibits attempts to design Drug Specificity; additionally, in order to define physiological functions for the cyclophilins, definitive isoform characterization is required. In the current study, enzymatic activity was assayed for 15 of the 17 human cyclophilin isomerase domains, and binding to the cyclosporin scaffold was tested. In order to rationalize the observed isoform diversity, the high-resolution crystallographic structures of seven cyclophilin domains were determined. These models, combined with seven previously solved cyclophilin isoforms, provide the basis for a family-wide structure:function analysis. Detailed structural analysis of the human cyclophilin isomerase explains why cyclophilin activity against short peptides is correlated with an ability to ligate cyclosporin and why certain isoforms are not competent for either activity. In addition, we find that regions of the isomerase domain outside the proline-binding surface impart isoform Specificity for both in vivo substrates and Drug design. We hypothesize that there is a well-defined molecular surface corresponding to the substrate-binding S2 position that is a site of diversity in the cyclophilin family. Computational simulations of substrate binding in thi
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structural and biochemical characterization of the human cyclophilin family of peptidyl prolyl isomerases
PLOS Biology, 2010Co-Authors: Tara L Davis, John R Walker, Valerie Campagnaslater, P J Finerty, Ragika Paramanathan, Galina Bernstein, F Mackenzie, Wolfram Tempel, Hui Ouyang, Wen Hwa LeeAbstract:Peptidyl-prolyl isomerases catalyze the conversion between cis and trans isomers of proline. The cyclophilin family of peptidyl-prolyl isomerases is well known for being the target of the immunosuppressive Drug cyclosporin, used to combat organ transplant rejection. There is great interest in both the substrate Specificity of these enzymes and the design of isoform-selective ligands for them. However, the dearth of available data for individual family members inhibits attempts to design Drug Specificity; additionally, in order to define physiological functions for the cyclophilins, definitive isoform characterization is required. In the current study, enzymatic activity was assayed for 15 of the 17 human cyclophilin isomerase domains, and binding to the cyclosporin scaffold was tested. In order to rationalize the observed isoform diversity, the high-resolution crystallographic structures of seven cyclophilin domains were determined. These models, combined with seven previously solved cyclophilin isoforms, provide the basis for a family-wide structure∶function analysis. Detailed structural analysis of the human cyclophilin isomerase explains why cyclophilin activity against short peptides is correlated with an ability to ligate cyclosporin and why certain isoforms are not competent for either activity. In addition, we find that regions of the isomerase domain outside the proline-binding surface impart isoform Specificity for both in vivo substrates and Drug design. We hypothesize that there is a well-defined molecular surface corresponding to the substrate-binding S2 position that is a site of diversity in the cyclophilin family. Computational simulations of substrate binding in this region support our observations. Our data indicate that unique isoform determinants exist that may be exploited for development of selective ligands and suggest that the currently available small-molecule and peptide-based ligands for this class of enzyme are insufficient for isoform Specificity. Enhanced version This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3-D representations and animated transitions. Please note that a Web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
Anthony L. Riley - One of the best experts on this subject based on the ideXlab platform.
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Pre-exposure to cocaine or morphine attenuates taste avoidance conditioning in adolescent rats: Drug Specificity in the US pre-exposure effect.
Developmental psychobiology, 2017Co-Authors: Matthew M. Clasen, Briana J. Hempel, Anthony L. RileyAbstract:Although the attenuating effects of Drug history on conditioned taste avoidance (CTA) learning have been widely investigated in adults, such effects in adolescents have not been well characterized. Recent research has suggested that the display of the Drug pre-exposure effect during adolescence may be Drug dependent given that pre-exposure to ethanol attenuates subsequent conditioning, whereas pre-exposure to the classic emetic lithium chloride (LiCl) fails to do so. The present study began investigating the possible Drug-dependent nature of the effects of Drug pre-exposure by pre-exposing and conditioning adolescent male Sprague-Dawley rats to Drugs from two additional classes, specifically psychostimulants (cocaine; Experiment 1) and opioids (morphine; Experiment 2). Consistent with prior work with ethanol (but not LiCl), prior exposure to both cocaine and morphine attenuated taste avoidance induced by these compounds. Although this work supports the view of Drug-dependent pre-exposure effects on taste avoidance learning during adolescence, research is needed to assess its mechanisms.
Tara L Davis - One of the best experts on this subject based on the ideXlab platform.
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Structural and Biochemical Characterization of the Human Cyclophilin Family of Peptidyl-Prolyl Isomerases
2016Co-Authors: Tara L Davis, Elan Z Eisenmesser, John R Walker, P J Finerty, Galina Bernstein, F Mackenzie, Wolfram Tempel, Hui Ouyang, Wen Hwa Lee, Sirano Dhe-paganonAbstract:Peptidyl-prolyl isomerases catalyze the conversion between cis and trans isomers of proline. The cyclophilin family of peptidyl-prolyl isomerases is well known for being the target of the immunosuppressive Drug cyclosporin, used to combat organ transplant rejection. There is great interest in both the substrate Specificity of these enzymes and the design of isoform-selective ligands for them. However, the dearth of available data for individual family members inhibits attempts to design Drug Specificity; additionally, in order to define physiological functions for the cyclophilins, definitive isoform characterization is required. In the current study, enzymatic activity was assayed for 15 of the 17 human cyclophilin isomerase domains, and binding to the cyclosporin scaffold was tested. In order to rationalize the observed isoform diversity, the high-resolution crystallographic structures of seven cyclophilin domains were determined. These models, combined with seven previously solved cyclophilin isoforms, provide the basis for a family-wide structure:function analysis. Detailed structural analysis of the human cyclophilin isomerase explains why cyclophilin activity against short peptides is correlated with an ability to ligate cyclosporin and why certain isoforms are not competent for either activity. In addition, we find that regions of the isomerase domain outside the proline-binding surface impart isoform Specificity for both in vivo substrates and Drug design. We hypothesize that there is a well-defined molecular surface corresponding to the substrate-binding S2 position that is a site of diversity in the cyclophilin family. Computational simulations of substrate binding in thi
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structural and biochemical characterization of the human cyclophilin family of peptidyl prolyl isomerases
PLOS Biology, 2010Co-Authors: Tara L Davis, John R Walker, Valerie Campagnaslater, P J Finerty, Ragika Paramanathan, Galina Bernstein, F Mackenzie, Wolfram Tempel, Hui Ouyang, Wen Hwa LeeAbstract:Peptidyl-prolyl isomerases catalyze the conversion between cis and trans isomers of proline. The cyclophilin family of peptidyl-prolyl isomerases is well known for being the target of the immunosuppressive Drug cyclosporin, used to combat organ transplant rejection. There is great interest in both the substrate Specificity of these enzymes and the design of isoform-selective ligands for them. However, the dearth of available data for individual family members inhibits attempts to design Drug Specificity; additionally, in order to define physiological functions for the cyclophilins, definitive isoform characterization is required. In the current study, enzymatic activity was assayed for 15 of the 17 human cyclophilin isomerase domains, and binding to the cyclosporin scaffold was tested. In order to rationalize the observed isoform diversity, the high-resolution crystallographic structures of seven cyclophilin domains were determined. These models, combined with seven previously solved cyclophilin isoforms, provide the basis for a family-wide structure∶function analysis. Detailed structural analysis of the human cyclophilin isomerase explains why cyclophilin activity against short peptides is correlated with an ability to ligate cyclosporin and why certain isoforms are not competent for either activity. In addition, we find that regions of the isomerase domain outside the proline-binding surface impart isoform Specificity for both in vivo substrates and Drug design. We hypothesize that there is a well-defined molecular surface corresponding to the substrate-binding S2 position that is a site of diversity in the cyclophilin family. Computational simulations of substrate binding in this region support our observations. Our data indicate that unique isoform determinants exist that may be exploited for development of selective ligands and suggest that the currently available small-molecule and peptide-based ligands for this class of enzyme are insufficient for isoform Specificity. Enhanced version This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3-D representations and animated transitions. Please note that a Web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
Robert Luxenhofer - One of the best experts on this subject based on the ideXlab platform.
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Drug Specificity synergy and antagonism in ultrahigh capacity poly 2 oxazoline poly 2 oxazine based formulations
Journal of the American Chemical Society, 2017Co-Authors: Michael M Lubtow, Lukas Hahn, Malik Salman Haider, Robert LuxenhoferAbstract:Polymer micelles offer the possibility to create a nanoscopic environment that is distinct from the bulk phase. They find applications in catalysis, Drug delivery, cleaning, etc. Often, one simply distinguishes between hydrophilic and hydrophobic, but fine-tuning of the microenvironment is possible by adjusting the structure of the polymer amphiphile. Here, we investigated a small library of structurally similar amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s with respect to their solubilization capacity for two extremely water insoluble Drugs, curcumin and paclitaxel. We found very significant and orthogonal specificities even if only one methylene group is exchanged between the polymer backbone and side chain. More strikingly, we observed profound synergistic and antagonistic solubilization patterns for the coformulation of the two Drugs. Our findings shed new light on host–guest interaction in polymer micelles and such pronounced host–guest specificities in polymer micelles may not only be...
Matthew M. Clasen - One of the best experts on this subject based on the ideXlab platform.
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Pre-exposure to cocaine or morphine attenuates taste avoidance conditioning in adolescent rats: Drug Specificity in the US pre-exposure effect.
Developmental psychobiology, 2017Co-Authors: Matthew M. Clasen, Briana J. Hempel, Anthony L. RileyAbstract:Although the attenuating effects of Drug history on conditioned taste avoidance (CTA) learning have been widely investigated in adults, such effects in adolescents have not been well characterized. Recent research has suggested that the display of the Drug pre-exposure effect during adolescence may be Drug dependent given that pre-exposure to ethanol attenuates subsequent conditioning, whereas pre-exposure to the classic emetic lithium chloride (LiCl) fails to do so. The present study began investigating the possible Drug-dependent nature of the effects of Drug pre-exposure by pre-exposing and conditioning adolescent male Sprague-Dawley rats to Drugs from two additional classes, specifically psychostimulants (cocaine; Experiment 1) and opioids (morphine; Experiment 2). Consistent with prior work with ethanol (but not LiCl), prior exposure to both cocaine and morphine attenuated taste avoidance induced by these compounds. Although this work supports the view of Drug-dependent pre-exposure effects on taste avoidance learning during adolescence, research is needed to assess its mechanisms.
