Conserved hydrogen bonds and water molecules in MDR HIV-1 protease substrate complexes.
Biochem Biophys Res Commun
; 430(3): 1022-7, 2013 Jan 18.
Article
en En
| MEDLINE
| ID: mdl-23261453
ABSTRACT
The success of highly active antiretroviral therapy (HAART) in anti-HIV therapy is severely compromised by the rapidly developing drug resistance. HIV-1 protease inhibitors, part of HAART, are losing their potency and efficacy in inhibiting the target. Multi-drug resistant (MDR) 769 HIV-1 protease (resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84, 90) was selected for the present study to understand the binding to its natural substrates. The nine crystal structures of MDR769 HIV-1 protease substrate hepta-peptide complexes were analyzed in order to reveal the conserved structural elements for the purpose of drug design against MDR HIV-1 protease. Our structural studies demonstrated that highly conserved hydrogen bonds between the protease and substrate peptides, together with the conserved crystallographic water molecules, played a crucial role in the substrate recognition, substrate stabilization and protease stabilization. In addition, the absence of the key flap-ligand bridging water molecule might imply a different catalytic mechanism of MDR769 HIV-1 protease compared to that of wild type (WT) HIV-1 protease.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Agua
/
Proteasa del VIH
/
Farmacorresistencia Viral Múltiple
Límite:
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos