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Mind the Metal: A Fragment Library-Derived Zinc Impurity Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural Rearrangements
[Image: see text] Efforts to develop inhibitors, activators, and effectors of biological reactions using small molecule libraries are often hampered by interference compounds, artifacts, and false positives that permeate the pool of initial hits. Here, we report the discovery of a promising initial...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663392/ https://www.ncbi.nlm.nih.gov/pubmed/28933844 http://dx.doi.org/10.1021/acs.jmedchem.7b01071 |
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author | Morreale, Francesca E. Testa, Andrea Chaugule, Viduth K. Bortoluzzi, Alessio Ciulli, Alessio Walden, Helen |
author_facet | Morreale, Francesca E. Testa, Andrea Chaugule, Viduth K. Bortoluzzi, Alessio Ciulli, Alessio Walden, Helen |
author_sort | Morreale, Francesca E. |
collection | PubMed |
description | [Image: see text] Efforts to develop inhibitors, activators, and effectors of biological reactions using small molecule libraries are often hampered by interference compounds, artifacts, and false positives that permeate the pool of initial hits. Here, we report the discovery of a promising initial hit compound targeting the Fanconi anemia ubiquitin-conjugating enzyme Ube2T and describe its biophysical and biochemical characterization. Analysis of the co-crystal structure led to the identification of a contaminating zinc ion as solely responsible for the observed effects. Zinc binding to the active site cysteine induces a domain swap in Ube2T that leads to cyclic trimerization organized in an open-ended linear assembly. Our study serves as a cautionary tale for screening small molecule libraries and provides insights into the structural plasticity of ubiquitin-conjugating enzymes. |
format | Online Article Text |
id | pubmed-5663392 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-56633922017-11-01 Mind the Metal: A Fragment Library-Derived Zinc Impurity Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural Rearrangements Morreale, Francesca E. Testa, Andrea Chaugule, Viduth K. Bortoluzzi, Alessio Ciulli, Alessio Walden, Helen J Med Chem [Image: see text] Efforts to develop inhibitors, activators, and effectors of biological reactions using small molecule libraries are often hampered by interference compounds, artifacts, and false positives that permeate the pool of initial hits. Here, we report the discovery of a promising initial hit compound targeting the Fanconi anemia ubiquitin-conjugating enzyme Ube2T and describe its biophysical and biochemical characterization. Analysis of the co-crystal structure led to the identification of a contaminating zinc ion as solely responsible for the observed effects. Zinc binding to the active site cysteine induces a domain swap in Ube2T that leads to cyclic trimerization organized in an open-ended linear assembly. Our study serves as a cautionary tale for screening small molecule libraries and provides insights into the structural plasticity of ubiquitin-conjugating enzymes. American Chemical Society 2017-09-21 2017-10-12 /pmc/articles/PMC5663392/ /pubmed/28933844 http://dx.doi.org/10.1021/acs.jmedchem.7b01071 Text en Copyright © 2017 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Morreale, Francesca E. Testa, Andrea Chaugule, Viduth K. Bortoluzzi, Alessio Ciulli, Alessio Walden, Helen Mind the Metal: A Fragment Library-Derived Zinc Impurity Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural Rearrangements |
title | Mind the Metal:
A Fragment Library-Derived Zinc Impurity
Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural
Rearrangements |
title_full | Mind the Metal:
A Fragment Library-Derived Zinc Impurity
Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural
Rearrangements |
title_fullStr | Mind the Metal:
A Fragment Library-Derived Zinc Impurity
Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural
Rearrangements |
title_full_unstemmed | Mind the Metal:
A Fragment Library-Derived Zinc Impurity
Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural
Rearrangements |
title_short | Mind the Metal:
A Fragment Library-Derived Zinc Impurity
Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural
Rearrangements |
title_sort | mind the metal:
a fragment library-derived zinc impurity
binds the e2 ubiquitin-conjugating enzyme ube2t and induces structural
rearrangements |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663392/ https://www.ncbi.nlm.nih.gov/pubmed/28933844 http://dx.doi.org/10.1021/acs.jmedchem.7b01071 |
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