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...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22844485/?tool=EBI |
| _version_ | 1818723002976567296 |
|---|---|
| author | Rebecca Swett G Andrés Cisneros Andrew L Feig |
| author_facet | Rebecca Swett G Andrés Cisneros Andrew L Feig |
| author_sort | Rebecca Swett |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-17T21:03:36Z |
| format | Article |
| id | doaj.art-abefd2e4b56542878f07cd49b993affe |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T21:03:36Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-abefd2e4b56542878f07cd49b993affe2022-12-21T21:32:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0177e4151810.1371/journal.pone.0041518Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition.Rebecca SwettG Andrés CisnerosAndrew L FeigClostridium 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22844485/?tool=EBI |
| spellingShingle | Rebecca Swett G Andrés Cisneros Andrew L Feig Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition. PLoS ONE |
| title | 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_short | 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22844485/?tool=EBI |
| work_keys_str_mv | AT rebeccaswett conformationalanalysisofclostridiumdifficiletoxinbanditsimplicationsforsubstraterecognition AT gandrescisneros conformationalanalysisofclostridiumdifficiletoxinbanditsimplicationsforsubstraterecognition AT andrewlfeig conformationalanalysisofclostridiumdifficiletoxinbanditsimplicationsforsubstraterecognition |