Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition.

Clostridium difficile (C. difficile) is an opportunistic pathogen that can cause potentially lethal hospital-acquired infections. The cellular damage that it causes is the result of two large clostridial cytotoxins: TcdA and TcdB which act by glucosylating cytosolic G-proteins, mis-regulation of whi...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Rebecca Swett, G Andrés Cisneros, Andrew L Feig
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/abefd2e4b56542878f07cd49b993affe
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:abefd2e4b56542878f07cd49b993affe
record_format	dspace
spelling	oai:doaj.org-article:abefd2e4b56542878f07cd49b993affe2021-11-18T07:11:30ZConformational analysis of Clostridium difficile toxin B and its implications for substrate recognition.1932-620310.1371/journal.pone.0041518https://doaj.org/article/abefd2e4b56542878f07cd49b993affe2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22844485/?tool=EBIhttps://doaj.org/toc/1932-6203Clostridium difficile (C. difficile) is an opportunistic pathogen that can cause potentially lethal hospital-acquired infections. The cellular damage that it causes is the result of two large clostridial cytotoxins: TcdA and TcdB which act by glucosylating cytosolic G-proteins, mis-regulation of which induces apoptosis. TcdB is a large flexible protein that appears to undergo significant structural rearrangement upon accommodation of its substrates: UDP-glucose and a Rho-family GTPase. To characterize the conformational space of TcdB, we applied normal mode and hinge-region analysis, followed by long-timescale unbiased molecular dynamics. In order to examine the TcdB and RhoA interaction, macromolecular docking and simulation of the TcdB/RhoA complex was performed. Generalized Masked Delaunay analysis of the simulations determined the extent of significant motions. This combination of methods elucidated a wide range of motions within TcdB that are reiterated in both the low-cost normal mode analysis and the extensive MD simulation. Of particular interest are the coupled motions between a peripheral 4-helix bundle and a small loop in the active site that must rearrange to allow RhoA entry to the catalytic site. These extensive coupled motions are indicative of TcdB using a conformational capture mechanism for substrate accommodation.Rebecca SwettG Andrés CisnerosAndrew L FeigPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e41518 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rebecca Swett G Andrés Cisneros Andrew L Feig Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition.
description	Clostridium difficile (C. difficile) is an opportunistic pathogen that can cause potentially lethal hospital-acquired infections. The cellular damage that it causes is the result of two large clostridial cytotoxins: TcdA and TcdB which act by glucosylating cytosolic G-proteins, mis-regulation of which induces apoptosis. TcdB is a large flexible protein that appears to undergo significant structural rearrangement upon accommodation of its substrates: UDP-glucose and a Rho-family GTPase. To characterize the conformational space of TcdB, we applied normal mode and hinge-region analysis, followed by long-timescale unbiased molecular dynamics. In order to examine the TcdB and RhoA interaction, macromolecular docking and simulation of the TcdB/RhoA complex was performed. Generalized Masked Delaunay analysis of the simulations determined the extent of significant motions. This combination of methods elucidated a wide range of motions within TcdB that are reiterated in both the low-cost normal mode analysis and the extensive MD simulation. Of particular interest are the coupled motions between a peripheral 4-helix bundle and a small loop in the active site that must rearrange to allow RhoA entry to the catalytic site. These extensive coupled motions are indicative of TcdB using a conformational capture mechanism for substrate accommodation.
format	article
author	Rebecca Swett G Andrés Cisneros Andrew L Feig
author_facet	Rebecca Swett G Andrés Cisneros Andrew L Feig
author_sort	Rebecca Swett
title	Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition.
title_short	Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition.
title_full	Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition.
title_fullStr	Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition.
title_full_unstemmed	Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition.
title_sort	conformational analysis of clostridium difficile toxin b and its implications for substrate recognition.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/abefd2e4b56542878f07cd49b993affe
work_keys_str_mv	AT rebeccaswett conformationalanalysisofclostridiumdifficiletoxinbanditsimplicationsforsubstraterecognition AT gandrescisneros conformationalanalysisofclostridiumdifficiletoxinbanditsimplicationsforsubstraterecognition AT andrewlfeig conformationalanalysisofclostridiumdifficiletoxinbanditsimplicationsforsubstraterecognition
_version_	1718423807634440192

Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition.

Ejemplares similares