Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite

Autores
Gutierrez, Lucas Joel; Andujar, Sebastian Antonio; Enriz, Ricardo Daniel; Baldoni, Hector Armando
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
A molecular modeling study giving structural, functional, and mutagenesis insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite is reported. Our results allow extending experimental data resulting from X-ray dif- fraction experiments in order to examine unknown aspects for the Fab-BACE1 recognition and its binding mode. Thus, the study performed here allows extending the inherently static nature of crystallographic structures in order to gain a deeper understanding of the structural and dynamical basis at the atomic level. The characteristics and strength of the interatomic interactions involved in the immune complex formation are exhaustively analyzed. The results might explain how the anti-BACE1 Fab fragment and other BACE1 exosite binders are capable to produce an allosteric modulation of the BACE1 activity. Our site-directed mutagenesis study indicated that the functional anti-BACE1 paratope, residues Tyr32 (H1), Trp50 (H2), Arg98 (H3), Phe101 (H3), Trp104 (H3) and Tyr94 (L3), strongly dominates the binding ener- getics with the BACE1 exosite. The mutational studies described in this work might accelerate the development of new BACE1 exosite binders with interesting pharmacological activity.
Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Fil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidiciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Cs.fisico Matemáticas y Naturales. Instituto Multidiciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Matemática Aplicada de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Materia
Bace1
Alzheimer
Immune Complex
Allosteric Control
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/18557
Acceder
id CONICETDig_018e204a50bb9043c95c96f8af45b837
oai_identifier_str oai:ri.conicet.gov.ar:11336/18557
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exositeGutierrez, Lucas JoelAndujar, Sebastian AntonioEnriz, Ricardo DanielBaldoni, Hector ArmandoBace1AlzheimerImmune ComplexAllosteric Controlhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1A molecular modeling study giving structural, functional, and mutagenesis insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite is reported. Our results allow extending experimental data resulting from X-ray dif- fraction experiments in order to examine unknown aspects for the Fab-BACE1 recognition and its binding mode. Thus, the study performed here allows extending the inherently static nature of crystallographic structures in order to gain a deeper understanding of the structural and dynamical basis at the atomic level. The characteristics and strength of the interatomic interactions involved in the immune complex formation are exhaustively analyzed. The results might explain how the anti-BACE1 Fab fragment and other BACE1 exosite binders are capable to produce an allosteric modulation of the BACE1 activity. Our site-directed mutagenesis study indicated that the functional anti-BACE1 paratope, residues Tyr32 (H1), Trp50 (H2), Arg98 (H3), Phe101 (H3), Trp104 (H3) and Tyr94 (L3), strongly dominates the binding ener- getics with the BACE1 exosite. The mutational studies described in this work might accelerate the development of new BACE1 exosite binders with interesting pharmacological activity.Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; ArgentinaFil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; ArgentinaFil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidiciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Cs.fisico Matemáticas y Naturales. Instituto Multidiciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Matemática Aplicada de San Luis; Argentina. Universidad Nacional de San Luis; ArgentinaTaylor & Francis2014-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/18557Gutierrez, Lucas Joel; Andujar, Sebastian Antonio; Enriz, Ricardo Daniel; Baldoni, Hector Armando; Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite; Taylor & Francis; Journal Of Biomolecular Structure & Dynamics; 32; 9; 9-2014; 1421-14330739-1102enginfo:eu-repo/semantics/altIdentifier/url/http://www.tandfonline.com/doi/abs/10.1080/07391102.2013.821024?journalCode=tbsd20info:eu-repo/semantics/altIdentifier/doi/10.1080/07391102.2013.821024info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:17:13Zoai:ri.conicet.gov.ar:11336/18557instacron: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:34982025-10-22 12:17:14.05CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite
title Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite
spellingShingle Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite
Gutierrez, Lucas Joel
Bace1
Alzheimer
Immune Complex
Allosteric Control
title_short Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite
title_full Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite
title_fullStr Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite
title_full_unstemmed Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite
title_sort Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite
dc.creator.none.fl_str_mv Gutierrez, Lucas Joel
Andujar, Sebastian Antonio
Enriz, Ricardo Daniel
Baldoni, Hector Armando
author Gutierrez, Lucas Joel
author_facet Gutierrez, Lucas Joel
Andujar, Sebastian Antonio
Enriz, Ricardo Daniel
Baldoni, Hector Armando
author_role author
author2 Andujar, Sebastian Antonio
Enriz, Ricardo Daniel
Baldoni, Hector Armando
author2_role author
author
author
dc.subject.none.fl_str_mv Bace1
Alzheimer
Immune Complex
Allosteric Control
topic Bace1
Alzheimer
Immune Complex
Allosteric Control
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv A molecular modeling study giving structural, functional, and mutagenesis insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite is reported. Our results allow extending experimental data resulting from X-ray dif- fraction experiments in order to examine unknown aspects for the Fab-BACE1 recognition and its binding mode. Thus, the study performed here allows extending the inherently static nature of crystallographic structures in order to gain a deeper understanding of the structural and dynamical basis at the atomic level. The characteristics and strength of the interatomic interactions involved in the immune complex formation are exhaustively analyzed. The results might explain how the anti-BACE1 Fab fragment and other BACE1 exosite binders are capable to produce an allosteric modulation of the BACE1 activity. Our site-directed mutagenesis study indicated that the functional anti-BACE1 paratope, residues Tyr32 (H1), Trp50 (H2), Arg98 (H3), Phe101 (H3), Trp104 (H3) and Tyr94 (L3), strongly dominates the binding ener- getics with the BACE1 exosite. The mutational studies described in this work might accelerate the development of new BACE1 exosite binders with interesting pharmacological activity.
Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Fil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidiciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Cs.fisico Matemáticas y Naturales. Instituto Multidiciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Matemática Aplicada de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
description A molecular modeling study giving structural, functional, and mutagenesis insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite is reported. Our results allow extending experimental data resulting from X-ray dif- fraction experiments in order to examine unknown aspects for the Fab-BACE1 recognition and its binding mode. Thus, the study performed here allows extending the inherently static nature of crystallographic structures in order to gain a deeper understanding of the structural and dynamical basis at the atomic level. The characteristics and strength of the interatomic interactions involved in the immune complex formation are exhaustively analyzed. The results might explain how the anti-BACE1 Fab fragment and other BACE1 exosite binders are capable to produce an allosteric modulation of the BACE1 activity. Our site-directed mutagenesis study indicated that the functional anti-BACE1 paratope, residues Tyr32 (H1), Trp50 (H2), Arg98 (H3), Phe101 (H3), Trp104 (H3) and Tyr94 (L3), strongly dominates the binding ener- getics with the BACE1 exosite. The mutational studies described in this work might accelerate the development of new BACE1 exosite binders with interesting pharmacological activity.
publishDate 2014
dc.date.none.fl_str_mv 2014-09
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/11336/18557
Gutierrez, Lucas Joel; Andujar, Sebastian Antonio; Enriz, Ricardo Daniel; Baldoni, Hector Armando; Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite; Taylor & Francis; Journal Of Biomolecular Structure & Dynamics; 32; 9; 9-2014; 1421-1433
0739-1102
url http://hdl.handle.net/11336/18557
identifier_str_mv Gutierrez, Lucas Joel; Andujar, Sebastian Antonio; Enriz, Ricardo Daniel; Baldoni, Hector Armando; Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite; Taylor & Francis; Journal Of Biomolecular Structure & Dynamics; 32; 9; 9-2014; 1421-1433
0739-1102
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.tandfonline.com/doi/abs/10.1080/07391102.2013.821024?journalCode=tbsd20
info:eu-repo/semantics/altIdentifier/doi/10.1080/07391102.2013.821024
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
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Taylor & Francis
publisher.none.fl_str_mv Taylor & Francis
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv 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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score 12.968121

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