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Structural Dynamics of the Cereblon Ligand Binding Domain
Cereblon, a primary target of thalidomide and its derivatives, has been characterized structurally from both bacteria and animals. Especially well studied is the thalidomide binding domain, CULT, which shows an invariable structure across different organisms and in complex with different ligands. He...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449219/ https://www.ncbi.nlm.nih.gov/pubmed/26024445 http://dx.doi.org/10.1371/journal.pone.0128342 |
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author | Hartmann, Marcus D. Boichenko, Iuliia Coles, Murray Lupas, Andrei N. Hernandez Alvarez, Birte |
author_facet | Hartmann, Marcus D. Boichenko, Iuliia Coles, Murray Lupas, Andrei N. Hernandez Alvarez, Birte |
author_sort | Hartmann, Marcus D. |
collection | PubMed |
description | Cereblon, a primary target of thalidomide and its derivatives, has been characterized structurally from both bacteria and animals. Especially well studied is the thalidomide binding domain, CULT, which shows an invariable structure across different organisms and in complex with different ligands. Here, based on a series of crystal structures of a bacterial representative, we reveal the conformational flexibility and structural dynamics of this domain. In particular, we follow the unfolding of large fractions of the domain upon release of thalidomide in the crystalline state. Our results imply that a third of the domain, including the thalidomide binding pocket, only folds upon ligand binding. We further characterize the structural effect of the C-terminal truncation resulting from the mental-retardation linked R419X nonsense mutation in vitro and offer a mechanistic hypothesis for its irresponsiveness to thalidomide. At 1.2Å resolution, our data provide a view of thalidomide binding at atomic resolution. |
format | Online Article Text |
id | pubmed-4449219 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44492192015-06-09 Structural Dynamics of the Cereblon Ligand Binding Domain Hartmann, Marcus D. Boichenko, Iuliia Coles, Murray Lupas, Andrei N. Hernandez Alvarez, Birte PLoS One Research Article Cereblon, a primary target of thalidomide and its derivatives, has been characterized structurally from both bacteria and animals. Especially well studied is the thalidomide binding domain, CULT, which shows an invariable structure across different organisms and in complex with different ligands. Here, based on a series of crystal structures of a bacterial representative, we reveal the conformational flexibility and structural dynamics of this domain. In particular, we follow the unfolding of large fractions of the domain upon release of thalidomide in the crystalline state. Our results imply that a third of the domain, including the thalidomide binding pocket, only folds upon ligand binding. We further characterize the structural effect of the C-terminal truncation resulting from the mental-retardation linked R419X nonsense mutation in vitro and offer a mechanistic hypothesis for its irresponsiveness to thalidomide. At 1.2Å resolution, our data provide a view of thalidomide binding at atomic resolution. Public Library of Science 2015-05-29 /pmc/articles/PMC4449219/ /pubmed/26024445 http://dx.doi.org/10.1371/journal.pone.0128342 Text en © 2015 Hartmann et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Hartmann, Marcus D. Boichenko, Iuliia Coles, Murray Lupas, Andrei N. Hernandez Alvarez, Birte Structural Dynamics of the Cereblon Ligand Binding Domain |
title | Structural Dynamics of the Cereblon Ligand Binding Domain |
title_full | Structural Dynamics of the Cereblon Ligand Binding Domain |
title_fullStr | Structural Dynamics of the Cereblon Ligand Binding Domain |
title_full_unstemmed | Structural Dynamics of the Cereblon Ligand Binding Domain |
title_short | Structural Dynamics of the Cereblon Ligand Binding Domain |
title_sort | structural dynamics of the cereblon ligand binding domain |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449219/ https://www.ncbi.nlm.nih.gov/pubmed/26024445 http://dx.doi.org/10.1371/journal.pone.0128342 |
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