TY - JOUR
T1 - Conserved hydrogen bonds and water molecules in MDR HIV-1 protease substrate complexes
AU - Liu, Zhigang
AU - Wang, Yong
AU - Yedidi, Ravikiran S.
AU - Dewdney, Tamaria G.
AU - Reiter, Samuel J.
AU - Brunzelle, Joseph S.
AU - Kovari, Iulia A.
AU - Kovari, Ladislau C.
N1 - Funding Information:
This research was supported by the National Institutes of Health grant AI65294 and a grant from the American Foundation for AIDS Research (106457-34-RGGN).
PY - 2013/1/18
Y1 - 2013/1/18
N2 - 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.
AB - 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.
KW - Conserve hydrogen bonds and waters
KW - Crystallographic structure
KW - HIV-1 protease
KW - Multi-drug resistance
KW - Protease-substrate complex
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U2 - 10.1016/j.bbrc.2012.12.045
DO - 10.1016/j.bbrc.2012.12.045
M3 - Article
C2 - 23261453
AN - SCOPUS:84872492958
SN - 0006-291X
VL - 430
SP - 1022
EP - 1027
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -
