Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein

被引:1
|
作者
Romero, Atilio Reyes [1 ,2 ]
Kubica, Katarzyna [1 ]
Kitel, Radoslaw [1 ]
Rodriguez, Ismael [1 ]
Magiera-Mularz, Katarzyna [1 ]
Domling, Alexander [2 ]
Holak, Tad A. [1 ]
Surmiak, Ewa [1 ]
机构
[1] Jagiellonian Univ, Fac Chem, Dept Organ Chem, Gronostajowa 2, PL-30387 Krakow, Poland
[2] Univ Groningen, Dept Drug Design, A Deusinglaan 1, NL-9713 AV Groningen, Netherlands
来源
MOLECULES | 2022年 / 27卷 / 23期
关键词
protein-protein interactions; anti-cancer therapy; nuclear magnetic resonance; protein-peptide docking; small-molecule inhibitors; DRUG DISCOVERY; UBL5; GENE; UBIQUITIN; DOCKING; RECOGNITION; PEPTIDES; BINDING;
D O I
10.3390/molecules27238282
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:15
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