title: Conserved hydrogen bonds and water molecules in MDR HIV-1 protease substrate complexes.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine Detroit, MI 48201, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Ravikiran S
authors.initials: RS
authors.lastname: Yedidi
authors.forename: Tamaria G
authors.initials: TG
authors.lastname: Dewdney
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Reiter
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Brunzelle
authors.forename: Iulia A
authors.initials: IA
authors.lastname: Kovari
authors.forename: Ladislau C
authors.initials: LC
authors.lastname: Kovari
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D024921:Drug Resistance, Multiple, Viral; D004795:Enzyme Stability; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry; D011487:Protein Conformation; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry*
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D009842:Oligopeptides; D014867:Water; D016333:HIV Protease