Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Hartmann, Marcus D., Boichenko, Iuliia, Coles, Murray, Lupas, Andrei N., Hernandez Alvarez, Birte
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
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
_version_ 1782373831436926976
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
work_keys_str_mv AT hartmannmarcusd structuraldynamicsofthecereblonligandbindingdomain
AT boichenkoiuliia structuraldynamicsofthecereblonligandbindingdomain
AT colesmurray structuraldynamicsofthecereblonligandbindingdomain
AT lupasandrein structuraldynamicsofthecereblonligandbindingdomain
AT hernandezalvarezbirte structuraldynamicsofthecereblonligandbindingdomain