Pockets as structural descriptors of EGFR kinase conformations
- Autores
- Hasenahuer, Marcia Anahí; Barletta Roldan, Patricio German; Fernández Alberti, Sebastián; Parisi, Gustavo Daniel; Fornasari, Maria Silvina
- Año de publicación
- 2017
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Epidermal Growth Factor Receptor (EGFR), a tyrosine kinase receptor, is one of the main tumor markers in different types of cancers. The kinase native state is mainly composed of two populations of conformers: active and inactive. Several sequence variations in EGFR kinase region promote the differential enrichment of conformers with higher activity. Some structural characteristics have been proposed to differentiate kinase conformations, but these considerations could lead to ambiguous classifications. We present a structural characterisation of EGFR kinase conformers, focused on active site pocket comparisons, and the mapping of known pathological sequence variations. A structural based clustering of this pocket accurately discriminates active from inactive, well-characterised conformations. Furthermore, this main pocket contains, or is in close contact with, ≈65% of cancer-related variation positions. Although the relevance of protein dynamics to explain biological function has been extensively recognised, the usage of the ensemble of conformations in dynamic equilibrium to represent the functional state of proteins and the importance of pockets, cavities and/or tunnels was often neglected in previous studies. These functional structures and the equilibrium between them could be structurally analysed in wild type as well as in sequence variants. Our results indicate that biologically important pockets, as well as their shape and dynamics, are central to understanding protein function in wild-type, polymorphic or disease-related variations.
Fil: Hasenahuer, Marcia Anahí. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Barletta Roldan, Patricio German. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fernández Alberti, Sebastián. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Parisi, Gustavo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fornasari, Maria Silvina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina - Materia
-
STRUCTURAL BIOINFORMATICS
CONFORMATIONAL DIVERSITY
POCKETS AND CAVITIES
PROTEIN FUNCTION
EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) KINASE
DISEASE - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/41443
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Pockets as structural descriptors of EGFR kinase conformationsHasenahuer, Marcia AnahíBarletta Roldan, Patricio GermanFernández Alberti, SebastiánParisi, Gustavo DanielFornasari, Maria SilvinaSTRUCTURAL BIOINFORMATICSCONFORMATIONAL DIVERSITYPOCKETS AND CAVITIESPROTEIN FUNCTIONEPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) KINASEDISEASEhttps://purl.org/becyt/ford/1.2https://purl.org/becyt/ford/1Epidermal Growth Factor Receptor (EGFR), a tyrosine kinase receptor, is one of the main tumor markers in different types of cancers. The kinase native state is mainly composed of two populations of conformers: active and inactive. Several sequence variations in EGFR kinase region promote the differential enrichment of conformers with higher activity. Some structural characteristics have been proposed to differentiate kinase conformations, but these considerations could lead to ambiguous classifications. We present a structural characterisation of EGFR kinase conformers, focused on active site pocket comparisons, and the mapping of known pathological sequence variations. A structural based clustering of this pocket accurately discriminates active from inactive, well-characterised conformations. Furthermore, this main pocket contains, or is in close contact with, ≈65% of cancer-related variation positions. Although the relevance of protein dynamics to explain biological function has been extensively recognised, the usage of the ensemble of conformations in dynamic equilibrium to represent the functional state of proteins and the importance of pockets, cavities and/or tunnels was often neglected in previous studies. These functional structures and the equilibrium between them could be structurally analysed in wild type as well as in sequence variants. Our results indicate that biologically important pockets, as well as their shape and dynamics, are central to understanding protein function in wild-type, polymorphic or disease-related variations.Fil: Hasenahuer, Marcia Anahí. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barletta Roldan, Patricio German. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernández Alberti, Sebastián. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Parisi, Gustavo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fornasari, Maria Silvina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaPublic Library of Science2017-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/41443Hasenahuer, Marcia Anahí; Barletta Roldan, Patricio German; Fernández Alberti, Sebastián; Parisi, Gustavo Daniel; Fornasari, Maria Silvina; Pockets as structural descriptors of EGFR kinase conformations; Public Library of Science; Plos One; 12; 12; 12-2017; 1-17; e01891471932-6203CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://dx.plos.org/10.1371/journal.pone.0189147info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0189147info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:58:01Zoai:ri.conicet.gov.ar:11336/41443instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:58:02.059CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Pockets as structural descriptors of EGFR kinase conformations |
title |
Pockets as structural descriptors of EGFR kinase conformations |
spellingShingle |
Pockets as structural descriptors of EGFR kinase conformations Hasenahuer, Marcia Anahí STRUCTURAL BIOINFORMATICS CONFORMATIONAL DIVERSITY POCKETS AND CAVITIES PROTEIN FUNCTION EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) KINASE DISEASE |
title_short |
Pockets as structural descriptors of EGFR kinase conformations |
title_full |
Pockets as structural descriptors of EGFR kinase conformations |
title_fullStr |
Pockets as structural descriptors of EGFR kinase conformations |
title_full_unstemmed |
Pockets as structural descriptors of EGFR kinase conformations |
title_sort |
Pockets as structural descriptors of EGFR kinase conformations |
dc.creator.none.fl_str_mv |
Hasenahuer, Marcia Anahí Barletta Roldan, Patricio German Fernández Alberti, Sebastián Parisi, Gustavo Daniel Fornasari, Maria Silvina |
author |
Hasenahuer, Marcia Anahí |
author_facet |
Hasenahuer, Marcia Anahí Barletta Roldan, Patricio German Fernández Alberti, Sebastián Parisi, Gustavo Daniel Fornasari, Maria Silvina |
author_role |
author |
author2 |
Barletta Roldan, Patricio German Fernández Alberti, Sebastián Parisi, Gustavo Daniel Fornasari, Maria Silvina |
author2_role |
author author author author |
dc.subject.none.fl_str_mv |
STRUCTURAL BIOINFORMATICS CONFORMATIONAL DIVERSITY POCKETS AND CAVITIES PROTEIN FUNCTION EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) KINASE DISEASE |
topic |
STRUCTURAL BIOINFORMATICS CONFORMATIONAL DIVERSITY POCKETS AND CAVITIES PROTEIN FUNCTION EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) KINASE DISEASE |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.2 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Epidermal Growth Factor Receptor (EGFR), a tyrosine kinase receptor, is one of the main tumor markers in different types of cancers. The kinase native state is mainly composed of two populations of conformers: active and inactive. Several sequence variations in EGFR kinase region promote the differential enrichment of conformers with higher activity. Some structural characteristics have been proposed to differentiate kinase conformations, but these considerations could lead to ambiguous classifications. We present a structural characterisation of EGFR kinase conformers, focused on active site pocket comparisons, and the mapping of known pathological sequence variations. A structural based clustering of this pocket accurately discriminates active from inactive, well-characterised conformations. Furthermore, this main pocket contains, or is in close contact with, ≈65% of cancer-related variation positions. Although the relevance of protein dynamics to explain biological function has been extensively recognised, the usage of the ensemble of conformations in dynamic equilibrium to represent the functional state of proteins and the importance of pockets, cavities and/or tunnels was often neglected in previous studies. These functional structures and the equilibrium between them could be structurally analysed in wild type as well as in sequence variants. Our results indicate that biologically important pockets, as well as their shape and dynamics, are central to understanding protein function in wild-type, polymorphic or disease-related variations. Fil: Hasenahuer, Marcia Anahí. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Barletta Roldan, Patricio German. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Fernández Alberti, Sebastián. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Parisi, Gustavo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Fornasari, Maria Silvina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina |
description |
Epidermal Growth Factor Receptor (EGFR), a tyrosine kinase receptor, is one of the main tumor markers in different types of cancers. The kinase native state is mainly composed of two populations of conformers: active and inactive. Several sequence variations in EGFR kinase region promote the differential enrichment of conformers with higher activity. Some structural characteristics have been proposed to differentiate kinase conformations, but these considerations could lead to ambiguous classifications. We present a structural characterisation of EGFR kinase conformers, focused on active site pocket comparisons, and the mapping of known pathological sequence variations. A structural based clustering of this pocket accurately discriminates active from inactive, well-characterised conformations. Furthermore, this main pocket contains, or is in close contact with, ≈65% of cancer-related variation positions. Although the relevance of protein dynamics to explain biological function has been extensively recognised, the usage of the ensemble of conformations in dynamic equilibrium to represent the functional state of proteins and the importance of pockets, cavities and/or tunnels was often neglected in previous studies. These functional structures and the equilibrium between them could be structurally analysed in wild type as well as in sequence variants. Our results indicate that biologically important pockets, as well as their shape and dynamics, are central to understanding protein function in wild-type, polymorphic or disease-related variations. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-12 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/41443 Hasenahuer, Marcia Anahí; Barletta Roldan, Patricio German; Fernández Alberti, Sebastián; Parisi, Gustavo Daniel; Fornasari, Maria Silvina; Pockets as structural descriptors of EGFR kinase conformations; Public Library of Science; Plos One; 12; 12; 12-2017; 1-17; e0189147 1932-6203 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/41443 |
identifier_str_mv |
Hasenahuer, Marcia Anahí; Barletta Roldan, Patricio German; Fernández Alberti, Sebastián; Parisi, Gustavo Daniel; Fornasari, Maria Silvina; Pockets as structural descriptors of EGFR kinase conformations; Public Library of Science; Plos One; 12; 12; 12-2017; 1-17; e0189147 1932-6203 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://dx.plos.org/10.1371/journal.pone.0189147 info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0189147 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Public Library of Science |
publisher.none.fl_str_mv |
Public Library of Science |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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13.070432 |