The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops

Benjamin D. Kuiper, Bradley J. Keusch, Tamaria G. Dewdney, Poorvi Chordia, Kyla Ross, Joseph S. Brunzelle, Iulia A. Kovari, Rodger MacArthur, Hossein Salimnia, Ladislau C. Kovari

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

HIV-1 protease (PR) is a 99 amino acid protein responsible for proteolytic processing of the viral polyprotein - an essential step in the HIV-1 life cycle. Drug resistance mutations in PR that are selected during antiretroviral therapy lead to reduced efficacy of protease inhibitors (PI) including darunavir (DRV). To identify the structural mechanisms associated with the DRV resistance mutation L33F, we performed X-ray crystallographic studies with a multi-drug resistant HIV-1 protease isolate that contains the L33F mutation (MDR769 L33F). In contrast to other PR L33F DRV complexes, the structure of MDR769 L33F complexed with DRV reported here displays the protease flaps in an open conformation. The L33F mutation increases noncovalent interactions in the hydrophobic pocket of the PR compared to the wild-type (WT) structure. As a result, L33F appears to act as a molecular anchor, reducing the flexibility of the 30s loop (residues 29-35) and the 80s loop (residues 79-84). Molecular anchoring of the 30s and 80s loops leaves an open S1/S1' subsite and distorts the conserved hydrogen-bonding network of DRV. These findings are consistent with previous reports despite structural differences with regards to flap conformation.

Original languageEnglish (US)
Pages (from-to)160-165
Number of pages6
JournalBiochemistry and Biophysics Reports
Volume2
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

Fingerprint

Anchors
Peptide Hydrolases
Mutation
Conformations
Polyproteins
Hydrogen Bonding
Protease Inhibitors
Life Cycle Stages
Hydrophobic and Hydrophilic Interactions
Drug Resistance
Pharmaceutical Preparations
HIV-1
Life cycle
Hydrogen bonds
X-Rays
Darunavir
Human immunodeficiency virus 1 p16 protease
Amino Acids
X rays
Processing

Keywords

  • Darunavir
  • Drug resistance
  • HIV-1 protease
  • L33F
  • Molecular Anchor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

Cite this

The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops. / Kuiper, Benjamin D.; Keusch, Bradley J.; Dewdney, Tamaria G.; Chordia, Poorvi; Ross, Kyla; Brunzelle, Joseph S.; Kovari, Iulia A.; MacArthur, Rodger; Salimnia, Hossein; Kovari, Ladislau C.

In: Biochemistry and Biophysics Reports, Vol. 2, 01.07.2015, p. 160-165.

Research output: Contribution to journalArticle

Kuiper, Benjamin D. ; Keusch, Bradley J. ; Dewdney, Tamaria G. ; Chordia, Poorvi ; Ross, Kyla ; Brunzelle, Joseph S. ; Kovari, Iulia A. ; MacArthur, Rodger ; Salimnia, Hossein ; Kovari, Ladislau C. / The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops. In: Biochemistry and Biophysics Reports. 2015 ; Vol. 2. pp. 160-165.
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AU - Ross, Kyla

AU - Brunzelle, Joseph S.

AU - Kovari, Iulia A.

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AB - HIV-1 protease (PR) is a 99 amino acid protein responsible for proteolytic processing of the viral polyprotein - an essential step in the HIV-1 life cycle. Drug resistance mutations in PR that are selected during antiretroviral therapy lead to reduced efficacy of protease inhibitors (PI) including darunavir (DRV). To identify the structural mechanisms associated with the DRV resistance mutation L33F, we performed X-ray crystallographic studies with a multi-drug resistant HIV-1 protease isolate that contains the L33F mutation (MDR769 L33F). In contrast to other PR L33F DRV complexes, the structure of MDR769 L33F complexed with DRV reported here displays the protease flaps in an open conformation. The L33F mutation increases noncovalent interactions in the hydrophobic pocket of the PR compared to the wild-type (WT) structure. As a result, L33F appears to act as a molecular anchor, reducing the flexibility of the 30s loop (residues 29-35) and the 80s loop (residues 79-84). Molecular anchoring of the 30s and 80s loops leaves an open S1/S1' subsite and distorts the conserved hydrogen-bonding network of DRV. These findings are consistent with previous reports despite structural differences with regards to flap conformation.

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