An expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data.
Structure
; 32(8): 1231-1238.e4, 2024 Aug 08.
Article
em En
| MEDLINE
| ID: mdl-38861991
ABSTRACT
Due to their low binding affinities, detecting small-molecule fragments bound to protein structures from crystallographic datasets has been a challenge. Here, we report a trove of 65 new fragment hits for PTP1B, an "undruggable" therapeutic target enzyme for diabetes and cancer. These structures were obtained from computational analysis of data from a large crystallographic screen, demonstrating the power of this approach to elucidate many (â¼50% more) "hidden" ligand-bound states of proteins. Our new structures include a fragment hit found in a novel binding site in PTP1B with a unique location relative to the active site, one that links adjacent allosteric sites, and, perhaps most strikingly, a fragment that induces long-range allosteric protein conformational responses. Altogether, our research highlights the utility of computational analysis of crystallographic data, makes publicly available dozens of new ligand-bound structures of a high-value drug target, and identifies novel aspects of ligandability and allostery in PTP1B.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ligação Proteica
/
Sítio Alostérico
/
Proteína Tirosina Fosfatase não Receptora Tipo 1
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos