Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir

Yunfeng Tie, Andrey Y. Kovalevsky, Peter Boross, Yuan Fang Wang, Arun K. Ghosh, J. Tőzsér, Robert W. Harrison, Irene T. Weber

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Saquinavir (SQV), the first antiviral HIV-1 protease (PR) inhibitor approved for AIDS therapy, has been studied in complexes with PR and the variants PRI84V and PRV82A containing the single mutations I84V and V82A that provide resistance to all the clinical inhibitors. Atomic resolution crystal structures (0.97-1.25 Å) of the SQV complexes were analyzed in comparison to the protease complexes with darunavir, a new drug that targets resistant HIV, in order to understand the molecular basis of drug resistance. PRI84V and PRV82A complexes were obtained in both the space groups P21212 and P212 121, which provided experimental limits for the conformational flexibility. The SQV interactions with PR were very similar in the mutant complexes, consistent with the similar inhibition constants. The mutation from bigger to smaller amino acids allows more space to accommodate the large group at P1′ of SQV, unlike the reduced interactions observed in darunavir complexes. The residues 79-82 have adjusted to accommodate the large hydrophobic groups of SQV, suggesting that these residues are intrinsically flexible and their conformation depends more on the nature of the inhibitor than on the mutations in this region. This analysis will assist with development of more effective antiviral inhibitors.

Original languageEnglish
Pages (from-to)232-242
Number of pages11
JournalProteins: Structure, Function and Genetics
Volume67
Issue number1
DOIs
Publication statusPublished - Apr 2007

Fingerprint

Saquinavir
Crystal structure
Peptide Hydrolases
Mutation
Antiviral Agents
HIV Protease Inhibitors
Protease Inhibitors
Drug Resistance
Pharmaceutical Preparations
Conformations
Acquired Immunodeficiency Syndrome
Human immunodeficiency virus 1 p16 protease
HIV
Amino Acids

Keywords

  • AIDS
  • Darunavir
  • Drug resistance
  • Protease inhibitor

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

Cite this

Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir. / Tie, Yunfeng; Kovalevsky, Andrey Y.; Boross, Peter; Wang, Yuan Fang; Ghosh, Arun K.; Tőzsér, J.; Harrison, Robert W.; Weber, Irene T.

In: Proteins: Structure, Function and Genetics, Vol. 67, No. 1, 04.2007, p. 232-242.

Research output: Contribution to journalArticle

Tie, Yunfeng ; Kovalevsky, Andrey Y. ; Boross, Peter ; Wang, Yuan Fang ; Ghosh, Arun K. ; Tőzsér, J. ; Harrison, Robert W. ; Weber, Irene T. / Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir. In: Proteins: Structure, Function and Genetics. 2007 ; Vol. 67, No. 1. pp. 232-242.
@article{72d53c6155ce4e34b034592c4a39deb3,
title = "Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir",
abstract = "Saquinavir (SQV), the first antiviral HIV-1 protease (PR) inhibitor approved for AIDS therapy, has been studied in complexes with PR and the variants PRI84V and PRV82A containing the single mutations I84V and V82A that provide resistance to all the clinical inhibitors. Atomic resolution crystal structures (0.97-1.25 {\AA}) of the SQV complexes were analyzed in comparison to the protease complexes with darunavir, a new drug that targets resistant HIV, in order to understand the molecular basis of drug resistance. PRI84V and PRV82A complexes were obtained in both the space groups P21212 and P212 121, which provided experimental limits for the conformational flexibility. The SQV interactions with PR were very similar in the mutant complexes, consistent with the similar inhibition constants. The mutation from bigger to smaller amino acids allows more space to accommodate the large group at P1′ of SQV, unlike the reduced interactions observed in darunavir complexes. The residues 79-82 have adjusted to accommodate the large hydrophobic groups of SQV, suggesting that these residues are intrinsically flexible and their conformation depends more on the nature of the inhibitor than on the mutations in this region. This analysis will assist with development of more effective antiviral inhibitors.",
keywords = "AIDS, Darunavir, Drug resistance, Protease inhibitor",
author = "Yunfeng Tie and Kovalevsky, {Andrey Y.} and Peter Boross and Wang, {Yuan Fang} and Ghosh, {Arun K.} and J. Tőzs{\'e}r and Harrison, {Robert W.} and Weber, {Irene T.}",
year = "2007",
month = "4",
doi = "10.1002/prot.21304",
language = "English",
volume = "67",
pages = "232--242",
journal = "Proteins: Structure, Function and Genetics",
issn = "0887-3585",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir

AU - Tie, Yunfeng

AU - Kovalevsky, Andrey Y.

AU - Boross, Peter

AU - Wang, Yuan Fang

AU - Ghosh, Arun K.

AU - Tőzsér, J.

AU - Harrison, Robert W.

AU - Weber, Irene T.

PY - 2007/4

Y1 - 2007/4

N2 - Saquinavir (SQV), the first antiviral HIV-1 protease (PR) inhibitor approved for AIDS therapy, has been studied in complexes with PR and the variants PRI84V and PRV82A containing the single mutations I84V and V82A that provide resistance to all the clinical inhibitors. Atomic resolution crystal structures (0.97-1.25 Å) of the SQV complexes were analyzed in comparison to the protease complexes with darunavir, a new drug that targets resistant HIV, in order to understand the molecular basis of drug resistance. PRI84V and PRV82A complexes were obtained in both the space groups P21212 and P212 121, which provided experimental limits for the conformational flexibility. The SQV interactions with PR were very similar in the mutant complexes, consistent with the similar inhibition constants. The mutation from bigger to smaller amino acids allows more space to accommodate the large group at P1′ of SQV, unlike the reduced interactions observed in darunavir complexes. The residues 79-82 have adjusted to accommodate the large hydrophobic groups of SQV, suggesting that these residues are intrinsically flexible and their conformation depends more on the nature of the inhibitor than on the mutations in this region. This analysis will assist with development of more effective antiviral inhibitors.

AB - Saquinavir (SQV), the first antiviral HIV-1 protease (PR) inhibitor approved for AIDS therapy, has been studied in complexes with PR and the variants PRI84V and PRV82A containing the single mutations I84V and V82A that provide resistance to all the clinical inhibitors. Atomic resolution crystal structures (0.97-1.25 Å) of the SQV complexes were analyzed in comparison to the protease complexes with darunavir, a new drug that targets resistant HIV, in order to understand the molecular basis of drug resistance. PRI84V and PRV82A complexes were obtained in both the space groups P21212 and P212 121, which provided experimental limits for the conformational flexibility. The SQV interactions with PR were very similar in the mutant complexes, consistent with the similar inhibition constants. The mutation from bigger to smaller amino acids allows more space to accommodate the large group at P1′ of SQV, unlike the reduced interactions observed in darunavir complexes. The residues 79-82 have adjusted to accommodate the large hydrophobic groups of SQV, suggesting that these residues are intrinsically flexible and their conformation depends more on the nature of the inhibitor than on the mutations in this region. This analysis will assist with development of more effective antiviral inhibitors.

KW - AIDS

KW - Darunavir

KW - Drug resistance

KW - Protease inhibitor

UR - http://www.scopus.com/inward/record.url?scp=33847361008&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847361008&partnerID=8YFLogxK

U2 - 10.1002/prot.21304

DO - 10.1002/prot.21304

M3 - Article

C2 - 17243183

AN - SCOPUS:33847361008

VL - 67

SP - 232

EP - 242

JO - Proteins: Structure, Function and Genetics

JF - Proteins: Structure, Function and Genetics

SN - 0887-3585

IS - 1

ER -