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Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex

Cullin RING E3 ubiquitin ligases (CRLs) function in the ubiquitin proteasome system to catalyze the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins. CRLs are large dynamic complexes and attractive drug targets for the development of small-molecule inhibitors and chem...

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Autores principales: Cardote, Teresa A.F., Gadd, Morgan S., Ciulli, Alessio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462531/
https://www.ncbi.nlm.nih.gov/pubmed/28591624
http://dx.doi.org/10.1016/j.str.2017.04.009
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author Cardote, Teresa A.F.
Gadd, Morgan S.
Ciulli, Alessio
author_facet Cardote, Teresa A.F.
Gadd, Morgan S.
Ciulli, Alessio
author_sort Cardote, Teresa A.F.
collection PubMed
description Cullin RING E3 ubiquitin ligases (CRLs) function in the ubiquitin proteasome system to catalyze the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins. CRLs are large dynamic complexes and attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. The atomic details of whole CRL assembly and interactions that dictate subunit specificity remain elusive. Here we present the crystal structure of a pentameric CRL2(VHL) complex, composed of Cul2, Rbx1, Elongin B, Elongin C, and pVHL. The structure traps a closed state of full-length Cul2 and a new pose of Rbx1 in a trajectory from closed to open conformation. We characterize hotspots and binding thermodynamics at the interface between Cul2 and pVHL-EloBC and identify mutations that contribute toward a selectivity switch for Cul2 versus Cul5 recognition. Our findings provide structural and biophysical insights into the whole Cul2 complex that could aid future drug targeting.
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spelling pubmed-54625312017-06-15 Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex Cardote, Teresa A.F. Gadd, Morgan S. Ciulli, Alessio Structure Article Cullin RING E3 ubiquitin ligases (CRLs) function in the ubiquitin proteasome system to catalyze the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins. CRLs are large dynamic complexes and attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. The atomic details of whole CRL assembly and interactions that dictate subunit specificity remain elusive. Here we present the crystal structure of a pentameric CRL2(VHL) complex, composed of Cul2, Rbx1, Elongin B, Elongin C, and pVHL. The structure traps a closed state of full-length Cul2 and a new pose of Rbx1 in a trajectory from closed to open conformation. We characterize hotspots and binding thermodynamics at the interface between Cul2 and pVHL-EloBC and identify mutations that contribute toward a selectivity switch for Cul2 versus Cul5 recognition. Our findings provide structural and biophysical insights into the whole Cul2 complex that could aid future drug targeting. Cell Press 2017-06-06 /pmc/articles/PMC5462531/ /pubmed/28591624 http://dx.doi.org/10.1016/j.str.2017.04.009 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cardote, Teresa A.F.
Gadd, Morgan S.
Ciulli, Alessio
Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex
title Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex
title_full Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex
title_fullStr Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex
title_full_unstemmed Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex
title_short Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex
title_sort crystal structure of the cul2-rbx1-elobc-vhl ubiquitin ligase complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462531/
https://www.ncbi.nlm.nih.gov/pubmed/28591624
http://dx.doi.org/10.1016/j.str.2017.04.009
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