Conserved hydrogen bonds and water molecules in MDR HIV-1 protease substrate complexes

Journal Article · Wed Dec 19 04:00:00 EST 2012 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2012.12.045· OSTI ID:1061334

Liu, Zhigang ^[1]; Wang, Yong ^[2]; Yedidi, Ravikiran S. ^[3]; Dewdney, Tamaria G. ^[2]; Reiter, Samuel J. ^[2]; Brunzelle, Joseph S. ^[4]; Kovari, Iulia A. ^[2]; Kovari, Ladislau C. ^[2]

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1. Wayne State Univ., Detroit, MI (United States); Case Western Reserve Univ., Cleveland, OH (United States); Harbor Hospital Baltimore, MD (United States)
2. Wayne State Univ., Detroit, MI (United States)
3. Wayne State Univ., Detroit, MI (United States); National Institutes of Health, Bethesda, MD (United States)
4. Northwestern Univ. Feinberg School of Medicine, Chicago, IL (United States)

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. Additionally, 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.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: National Institutes of Health, New York, NY (United States)
• OSTI ID: 1061334
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: (3) ; 01, 2013 Vol. 430; ISSN 0006-291X
• Publisher: Elsevier
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

HIV-1
conserve hydrogen bonds and water
crystallographic structure
multi-drug resistance
protease-substrate complex