Structure-Based Analysis of Cryptic-Site Opening.
Structure
; 28(2): 223-235.e2, 2020 02 04.
Article
en En
| MEDLINE
| ID: mdl-31810712
ABSTRACT
Many proteins in their unbound structures have cryptic sites that are not appropriately sized for drug binding. We consider here 32 proteins from the recently published CryptoSite set with validated cryptic sites, and study whether the sites remain cryptic in all available X-ray structures of the proteins solved without any ligand bound near the sites. It was shown that only few of these proteins have binding pockets that never form without ligand binding. Sites that are cryptic in some structures but spontaneously form in others are also rare. In most proteins the forming of pockets is affected by mutations or ligand binding at locations far from the cryptic site. To further explore these mechanisms, we applied adiabatic biased molecular dynamics simulations to guide the proteins from their ligand-free structures to ligand-bound conformations, and studied the distribution of druggability scores of the pockets located at the cryptic sites.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Structure
Asunto de la revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
BIOTECNOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos