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Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein
By binding to the spliceosomal protein Snu66, the human ubiquitin-like protein Hub1 is a modulator of the spliceosome performance and facilitates alternative splicing. Small molecules that bind to Hub1 would be of interest to study the protein-protein interaction of Hub1/Snu66, which is linked to se...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9738620/ https://www.ncbi.nlm.nih.gov/pubmed/36500376 http://dx.doi.org/10.3390/molecules27238282 |
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author | Reyes Romero, Atilio Kubica, Katarzyna Kitel, Radoslaw Rodríguez, Ismael Magiera-Mularz, Katarzyna Dömling, Alexander Holak, Tad A. Surmiak, Ewa |
author_facet | Reyes Romero, Atilio Kubica, Katarzyna Kitel, Radoslaw Rodríguez, Ismael Magiera-Mularz, Katarzyna Dömling, Alexander Holak, Tad A. Surmiak, Ewa |
author_sort | Reyes Romero, Atilio |
collection | PubMed |
description | By binding to the spliceosomal protein Snu66, the human ubiquitin-like protein Hub1 is a modulator of the spliceosome performance and facilitates alternative splicing. Small molecules that bind to Hub1 would be of interest to study the protein-protein interaction of Hub1/Snu66, which is linked to several human pathologies, such as hypercholesterolemia, premature aging, neurodegenerative diseases, and cancer. To identify small molecule ligands for Hub1, we used the interface analysis, peptide modeling of the Hub1/Snu66 interaction and the fragment-based NMR screening. Fragment-based NMR screening has not proven sufficient to unambiguously search for fragments that bind to the Hub1 protein. This was because the Snu66 binding pocket of Hub1 is occupied by pH-sensitive residues, making it difficult to distinguish between pH-induced NMR shifts and actual binding events. The NMR analyses were therefore verified experimentally by microscale thermophoresis and by NMR pH titration experiments. Our study found two small peptides that showed binding to Hub1. These peptides are the first small-molecule ligands reported to interact with the Hub1 protein. |
format | Online Article Text |
id | pubmed-9738620 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97386202022-12-11 Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein Reyes Romero, Atilio Kubica, Katarzyna Kitel, Radoslaw Rodríguez, Ismael Magiera-Mularz, Katarzyna Dömling, Alexander Holak, Tad A. Surmiak, Ewa Molecules Article By binding to the spliceosomal protein Snu66, the human ubiquitin-like protein Hub1 is a modulator of the spliceosome performance and facilitates alternative splicing. Small molecules that bind to Hub1 would be of interest to study the protein-protein interaction of Hub1/Snu66, which is linked to several human pathologies, such as hypercholesterolemia, premature aging, neurodegenerative diseases, and cancer. To identify small molecule ligands for Hub1, we used the interface analysis, peptide modeling of the Hub1/Snu66 interaction and the fragment-based NMR screening. Fragment-based NMR screening has not proven sufficient to unambiguously search for fragments that bind to the Hub1 protein. This was because the Snu66 binding pocket of Hub1 is occupied by pH-sensitive residues, making it difficult to distinguish between pH-induced NMR shifts and actual binding events. The NMR analyses were therefore verified experimentally by microscale thermophoresis and by NMR pH titration experiments. Our study found two small peptides that showed binding to Hub1. These peptides are the first small-molecule ligands reported to interact with the Hub1 protein. MDPI 2022-11-28 /pmc/articles/PMC9738620/ /pubmed/36500376 http://dx.doi.org/10.3390/molecules27238282 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Reyes Romero, Atilio Kubica, Katarzyna Kitel, Radoslaw Rodríguez, Ismael Magiera-Mularz, Katarzyna Dömling, Alexander Holak, Tad A. Surmiak, Ewa Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein |
title | Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein |
title_full | Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein |
title_fullStr | Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein |
title_full_unstemmed | Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein |
title_short | Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein |
title_sort | computer- and nmr-aided design of small-molecule inhibitors of the hub1 protein |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9738620/ https://www.ncbi.nlm.nih.gov/pubmed/36500376 http://dx.doi.org/10.3390/molecules27238282 |
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