HSC70 has been identified as an important molecular target involved in the DF508-CFTR cystic fibrosis. HSC70 associates DF508-CFTR to a much greater extent than WT-CFTR and after this step, it recruits other co-chaperones (BAG1, CHIP) and performs the ubiquitination and proteosomal degradation of the protein. Up to now, several X-ray data concerning the HSC70:BAG1 complexes are available. Thus, we performed an ‘‘in silico’’ investigation focused to explore which different amino acid residues are involved in the binding of ATP, the natural substrate, and the co-crystallized ligands at the HSC70/BAG-1 interface. The study allowed us to evaluate sildenafil and KM11060, which proved to be also CFTR correctors, as potential HSC70:BAG1 inhibitors, and also let us derive interesting perspectives for the development of new CFTR correctors.
Scouting new molecular targets for CFTR therapy: the HSC70/BAG-1 complex. A computational study.
CICHERO, ELENA;MAZZEI, MAURO;FOSSA, PAOLA
2012-01-01
Abstract
HSC70 has been identified as an important molecular target involved in the DF508-CFTR cystic fibrosis. HSC70 associates DF508-CFTR to a much greater extent than WT-CFTR and after this step, it recruits other co-chaperones (BAG1, CHIP) and performs the ubiquitination and proteosomal degradation of the protein. Up to now, several X-ray data concerning the HSC70:BAG1 complexes are available. Thus, we performed an ‘‘in silico’’ investigation focused to explore which different amino acid residues are involved in the binding of ATP, the natural substrate, and the co-crystallized ligands at the HSC70/BAG-1 interface. The study allowed us to evaluate sildenafil and KM11060, which proved to be also CFTR correctors, as potential HSC70:BAG1 inhibitors, and also let us derive interesting perspectives for the development of new CFTR correctors.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
