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

Teresa A. F. Cardote; Morgan S. Gadd; Alessio Ciulli

doi:10.1016/j.str.2017.04.009

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

Teresa A. F. Cardote, Morgan S. Gadd, Alessio Ciulli (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

99 Citations (Scopus)

258 Downloads (Pure)

Abstract

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 CRL2VHL 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 vs. Cul5 recognition. Our findings provide structural and biophysical insights into whole Cul2 complex that could aid future drug targeting.

Original language	English
Pages (from-to)	901-911.e3
Number of pages	14
Journal	Structure
Volume	25
Issue number	6
DOIs	https://doi.org/10.1016/j.str.2017.04.009
Publication status	Published - 6 Jun 2017

Keywords

Cullin-RING E3 ubiquitin ligases
Protein-protein interactions
VHL
Cullin-2
RING domain proteins

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10.1016/j.str.2017.04.009Licence: CC BY

Final Published Version
© 2017 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 3.06 MBLicence: CC BY

DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)
Ciulli, A. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/05/13 → 30/04/18
Project: Research

Ligandability of protein-protein interactions and surfaces on Cullin RING E3 ubiquitin ligases
Cardote, T. A. D. F. (Author), Ciulli, A. (Supervisor), 2017
Student thesis: Doctoral Thesis › Doctor of Philosophy

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Ciulli, Alessio
- Centre for Targeted Protein Degradation - Professor of Chemical and Structural Biology
Person: Academic

Cite this

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title = "Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex",

abstract = "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 CRL2VHL 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 vs. Cul5 recognition. Our findings provide structural and biophysical insights into whole Cul2 complex that could aid future drug targeting.",

keywords = "Cullin-RING E3 ubiquitin ligases , Protein-protein interactions , VHL, Cullin-2, RING domain proteins",

author = "Cardote, {Teresa A. F.} and Gadd, {Morgan S.} and Alessio Ciulli",

note = "This work was supported by the European Research Council ERC-2012-StG-311460 DrugE3CRLs (Starting Grant to A.C.), and the Funda{\c c}{\~a}o para a Ci{\^e}ncia e Tecnologia SFRH/BD/92417/2013 (PhD Studentship to T.A.F.C.), and the Wellcome Trust (strategic awards 100476/Z/12/Z and 094090/Z/10/Z to the Division of BCDD).",

year = "2017",

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doi = "10.1016/j.str.2017.04.009",

language = "English",

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journal = "Structure",

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T1 - Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex

AU - Cardote, Teresa A. F.

AU - Gadd, Morgan S.

AU - Ciulli, Alessio

N1 - This work was supported by the European Research Council ERC-2012-StG-311460 DrugE3CRLs (Starting Grant to A.C.), and the Fundação para a Ciência e Tecnologia SFRH/BD/92417/2013 (PhD Studentship to T.A.F.C.), and the Wellcome Trust (strategic awards 100476/Z/12/Z and 094090/Z/10/Z to the Division of BCDD).

PY - 2017/6/6

Y1 - 2017/6/6

N2 - 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 CRL2VHL 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 vs. Cul5 recognition. Our findings provide structural and biophysical insights into whole Cul2 complex that could aid future drug targeting.

AB - 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 CRL2VHL 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 vs. Cul5 recognition. Our findings provide structural and biophysical insights into whole Cul2 complex that could aid future drug targeting.

KW - Cullin-RING E3 ubiquitin ligases

KW - Protein-protein interactions

KW - VHL

KW - Cullin-2

KW - RING domain proteins

U2 - 10.1016/j.str.2017.04.009

DO - 10.1016/j.str.2017.04.009

M3 - Article

C2 - 28591624

SN - 0969-2126

VL - 25

SP - 901-911.e3

JO - Structure

JF - Structure

IS - 6

ER -

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

Abstract

Keywords

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Projects

DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)

Student theses

Ligandability of protein-protein interactions and surfaces on Cullin RING E3 ubiquitin ligases

Profiles

Ciulli, Alessio

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