Construction of an engineered alpha 1-antitrypsin with inhibitory activity based on theoretical studies

Background: The elastase inhibitor α-1-antitrypsin (AAT), is a member of the serpin superfamily of protease inhibitors. AAT has a characteristic secondary structure of three-β-sheets, nine-α-helices and a reactive central loop (RCL). This protein inhibits target proteases...

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Autores principales:	Sangachini,Elham Dasi, Hasannia,Sadegh, Taghdir,Majid, Pirooznia,Nazanin, Ghadicholaei,Kamran Khalili
Lenguaje:	English
Publicado:	Pontificia Universidad Católica de Valparaíso 2012
Materias:	alpha1-antitrypsin molecular dynamic simulation Pichia pastoris
Acceso en línea:	http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-34582012000200008
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spelling	oai:scielo:S0717-345820120002000082012-06-06Construction of an engineered alpha 1-antitrypsin with inhibitory activity based on theoretical studiesSangachini,Elham DasiHasannia,SadeghTaghdir,MajidPirooznia,NazaninGhadicholaei,Kamran Khalili alpha1-antitrypsin molecular dynamic simulation Pichia pastoris Background: The elastase inhibitor α-1-antitrypsin (AAT), is a member of the serpin superfamily of protease inhibitors. AAT has a characteristic secondary structure of three-β-sheets, nine-α-helices and a reactive central loop (RCL). This protein inhibits target proteases by forming a stable complex in which the cleaved RCL is inserted into β-sheet-A of the serpin, leading to a conformational change in the AAT protein. Spontaneous polymerization and instability of AAT are challenges with regard to producing drugs against AAT-deficient diseases. Therefore, the purpose of many investigations currently is to produce drugs with lower degrees of polymerization and higher stabilities. In order to investigate the effect of the N-terminal segment (residues 1-43) on AAT structure, molecular dynamic (MD) simulation was used to study structural properties including Root-mean-square deviation (RMSD), internal motions, intramolecular non-bonded interactions and the total accessible surface area (ASA) of native and reduced AAT. These properties were compared in native and truncated AAT. Results: Theoretical studies showed no noticeable differences in the dynamic and structural properties of the two structures. These findings provided the basis for the experimental phase of the study in which sequences from the two AAT constructs were inserted into the expression vector pGAPZ and transformed into Pichia pastoris. Results showed no differences in the activities and polymerization of the two AAT constructs. Conclusions: As small-scale medicines are preferred by lung drug delivery systems, in this study AAT was designed and constructed by decreasing the number of amino acids at the N-terminal region.info:eu-repo/semantics/openAccessPontificia Universidad Católica de ValparaísoElectronic Journal of Biotechnology v.15 n.2 20122012-03-01text/htmlhttp://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-34582012000200008en
institution	Scielo Chile
collection	Scielo Chile
language	English
topic	alpha1-antitrypsin molecular dynamic simulation Pichia pastoris
spellingShingle	alpha1-antitrypsin molecular dynamic simulation Pichia pastoris Sangachini,Elham Dasi Hasannia,Sadegh Taghdir,Majid Pirooznia,Nazanin Ghadicholaei,Kamran Khalili Construction of an engineered alpha 1-antitrypsin with inhibitory activity based on theoretical studies
description	Background: The elastase inhibitor α-1-antitrypsin (AAT), is a member of the serpin superfamily of protease inhibitors. AAT has a characteristic secondary structure of three-β-sheets, nine-α-helices and a reactive central loop (RCL). This protein inhibits target proteases by forming a stable complex in which the cleaved RCL is inserted into β-sheet-A of the serpin, leading to a conformational change in the AAT protein. Spontaneous polymerization and instability of AAT are challenges with regard to producing drugs against AAT-deficient diseases. Therefore, the purpose of many investigations currently is to produce drugs with lower degrees of polymerization and higher stabilities. In order to investigate the effect of the N-terminal segment (residues 1-43) on AAT structure, molecular dynamic (MD) simulation was used to study structural properties including Root-mean-square deviation (RMSD), internal motions, intramolecular non-bonded interactions and the total accessible surface area (ASA) of native and reduced AAT. These properties were compared in native and truncated AAT. Results: Theoretical studies showed no noticeable differences in the dynamic and structural properties of the two structures. These findings provided the basis for the experimental phase of the study in which sequences from the two AAT constructs were inserted into the expression vector pGAPZ and transformed into Pichia pastoris. Results showed no differences in the activities and polymerization of the two AAT constructs. Conclusions: As small-scale medicines are preferred by lung drug delivery systems, in this study AAT was designed and constructed by decreasing the number of amino acids at the N-terminal region.
author	Sangachini,Elham Dasi Hasannia,Sadegh Taghdir,Majid Pirooznia,Nazanin Ghadicholaei,Kamran Khalili
author_facet	Sangachini,Elham Dasi Hasannia,Sadegh Taghdir,Majid Pirooznia,Nazanin Ghadicholaei,Kamran Khalili
author_sort	Sangachini,Elham Dasi
title	Construction of an engineered alpha 1-antitrypsin with inhibitory activity based on theoretical studies
title_short	Construction of an engineered alpha 1-antitrypsin with inhibitory activity based on theoretical studies
title_full	Construction of an engineered alpha 1-antitrypsin with inhibitory activity based on theoretical studies
title_fullStr	Construction of an engineered alpha 1-antitrypsin with inhibitory activity based on theoretical studies
title_full_unstemmed	Construction of an engineered alpha 1-antitrypsin with inhibitory activity based on theoretical studies
title_sort	construction of an engineered alpha 1-antitrypsin with inhibitory activity based on theoretical studies
publisher	Pontificia Universidad Católica de Valparaíso
publishDate	2012
url	http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-34582012000200008
work_keys_str_mv	AT sangachinielhamdasi constructionofanengineeredalpha1antitrypsinwithinhibitoryactivitybasedontheoreticalstudies AT hasanniasadegh constructionofanengineeredalpha1antitrypsinwithinhibitoryactivitybasedontheoreticalstudies AT taghdirmajid constructionofanengineeredalpha1antitrypsinwithinhibitoryactivitybasedontheoreticalstudies AT pirooznianazanin constructionofanengineeredalpha1antitrypsinwithinhibitoryactivitybasedontheoreticalstudies AT ghadicholaeikamrankhalili constructionofanengineeredalpha1antitrypsinwithinhibitoryactivitybasedontheoreticalstudies
_version_	1718441853741694976

Construction of an engineered alpha 1-antitrypsin with inhibitory activity based on theoretical studies

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