Structure and behavior of human α-Thrombin upon ligand recognition : thermodynamic and molecular dynamics studies
Autor(a) principal: | |
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Data de Publicação: | 2011 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/225287 |
Resumo: | Thrombin is a serine proteinase that plays a fundamental role in coagulation. In this study, we address the effects of ligand site recognition by alpha-thrombin on conformation and energetics in solution. Active site occupation induces large changes in secondary structure content in thrombin as shown by circular dichroism. Thrombin-D-Phe-Pro-Arg-chloromethyl ketone (PPACK) exhibits enhanced equilibrium and kinetic stability compared to free thrombin, whose difference is rooted in the unfolding step. Small-angle X-ray scattering (SAXS) measurements in solution reveal an overall similarity in the molecular envelope of thrombin and thrombin-PPACK, which differs from the crystal structure of thrombin. Molecular dynamics simulations performed with thrombin lead to different conformations than the one observed in the crystal structure. These data shed light on the diversity of thrombin conformers not previously observed in crystal structures with distinguished catalytic and conformational behaviors, which might have direct implications on novel strategies to design direct thrombin inhibitors. |
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Silva, Vivian de AlmeidaCargnelutti, Maria TherezaGiesel, Guilherme MenegonPalmieri, Leonardo C.Monteiro, Robson Q.Verli, HugoLima, Luis Mauricio Trambaioli da Rocha e2021-08-06T04:41:58Z20111932-6203http://hdl.handle.net/10183/225287000863177Thrombin is a serine proteinase that plays a fundamental role in coagulation. In this study, we address the effects of ligand site recognition by alpha-thrombin on conformation and energetics in solution. Active site occupation induces large changes in secondary structure content in thrombin as shown by circular dichroism. Thrombin-D-Phe-Pro-Arg-chloromethyl ketone (PPACK) exhibits enhanced equilibrium and kinetic stability compared to free thrombin, whose difference is rooted in the unfolding step. Small-angle X-ray scattering (SAXS) measurements in solution reveal an overall similarity in the molecular envelope of thrombin and thrombin-PPACK, which differs from the crystal structure of thrombin. Molecular dynamics simulations performed with thrombin lead to different conformations than the one observed in the crystal structure. These data shed light on the diversity of thrombin conformers not previously observed in crystal structures with distinguished catalytic and conformational behaviors, which might have direct implications on novel strategies to design direct thrombin inhibitors.application/pdfengPLoS ONE. San Francisco. Vol. 6, no. 9 (Sep. 2011), e24735, 12 p.TermodinâmicaDinâmica molecularStructure and behavior of human α-Thrombin upon ligand recognition : thermodynamic and molecular dynamics studiesEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT000863177.pdf.txt000863177.pdf.txtExtracted Texttext/plain62987http://www.lume.ufrgs.br/bitstream/10183/225287/2/000863177.pdf.txt53ad4aa9ba7057a1d79fd3176384bb55MD52ORIGINAL000863177.pdfTexto completo (inglês)application/pdf796681http://www.lume.ufrgs.br/bitstream/10183/225287/1/000863177.pdf166b167bf1a233ea062d7ca304e51bddMD5110183/2252872023-09-23 03:36:32.939123oai:www.lume.ufrgs.br:10183/225287Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2023-09-23T06:36:32Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Structure and behavior of human α-Thrombin upon ligand recognition : thermodynamic and molecular dynamics studies |
title |
Structure and behavior of human α-Thrombin upon ligand recognition : thermodynamic and molecular dynamics studies |
spellingShingle |
Structure and behavior of human α-Thrombin upon ligand recognition : thermodynamic and molecular dynamics studies Silva, Vivian de Almeida Termodinâmica Dinâmica molecular |
title_short |
Structure and behavior of human α-Thrombin upon ligand recognition : thermodynamic and molecular dynamics studies |
title_full |
Structure and behavior of human α-Thrombin upon ligand recognition : thermodynamic and molecular dynamics studies |
title_fullStr |
Structure and behavior of human α-Thrombin upon ligand recognition : thermodynamic and molecular dynamics studies |
title_full_unstemmed |
Structure and behavior of human α-Thrombin upon ligand recognition : thermodynamic and molecular dynamics studies |
title_sort |
Structure and behavior of human α-Thrombin upon ligand recognition : thermodynamic and molecular dynamics studies |
author |
Silva, Vivian de Almeida |
author_facet |
Silva, Vivian de Almeida Cargnelutti, Maria Thereza Giesel, Guilherme Menegon Palmieri, Leonardo C. Monteiro, Robson Q. Verli, Hugo Lima, Luis Mauricio Trambaioli da Rocha e |
author_role |
author |
author2 |
Cargnelutti, Maria Thereza Giesel, Guilherme Menegon Palmieri, Leonardo C. Monteiro, Robson Q. Verli, Hugo Lima, Luis Mauricio Trambaioli da Rocha e |
author2_role |
author author author author author author |
dc.contributor.author.fl_str_mv |
Silva, Vivian de Almeida Cargnelutti, Maria Thereza Giesel, Guilherme Menegon Palmieri, Leonardo C. Monteiro, Robson Q. Verli, Hugo Lima, Luis Mauricio Trambaioli da Rocha e |
dc.subject.por.fl_str_mv |
Termodinâmica Dinâmica molecular |
topic |
Termodinâmica Dinâmica molecular |
description |
Thrombin is a serine proteinase that plays a fundamental role in coagulation. In this study, we address the effects of ligand site recognition by alpha-thrombin on conformation and energetics in solution. Active site occupation induces large changes in secondary structure content in thrombin as shown by circular dichroism. Thrombin-D-Phe-Pro-Arg-chloromethyl ketone (PPACK) exhibits enhanced equilibrium and kinetic stability compared to free thrombin, whose difference is rooted in the unfolding step. Small-angle X-ray scattering (SAXS) measurements in solution reveal an overall similarity in the molecular envelope of thrombin and thrombin-PPACK, which differs from the crystal structure of thrombin. Molecular dynamics simulations performed with thrombin lead to different conformations than the one observed in the crystal structure. These data shed light on the diversity of thrombin conformers not previously observed in crystal structures with distinguished catalytic and conformational behaviors, which might have direct implications on novel strategies to design direct thrombin inhibitors. |
publishDate |
2011 |
dc.date.issued.fl_str_mv |
2011 |
dc.date.accessioned.fl_str_mv |
2021-08-06T04:41:58Z |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10183/225287 |
dc.identifier.issn.pt_BR.fl_str_mv |
1932-6203 |
dc.identifier.nrb.pt_BR.fl_str_mv |
000863177 |
identifier_str_mv |
1932-6203 000863177 |
url |
http://hdl.handle.net/10183/225287 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
PLoS ONE. San Francisco. Vol. 6, no. 9 (Sep. 2011), e24735, 12 p. |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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