PDBsum entry 3oxc

Hydrolase/hydrolase inhibitor

PDB id: 3oxc

Contents

Protein chains

99 a.a. *

Ligands

ROC

FMT ×2

SO4 ×2

Waters ×201

* Residue conservation analysis

PDB id:

3oxc

Name:

Hydrolase/hydrolase inhibitor

Title:

Wild type HIV-1 protease with antiviral drug saquinavir

Structure:

Protease. Chain: a, b. Fragment: residues 500-598. Engineered: yes. Mutation: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: pol. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.16Å R-factor: 0.139 R-free: 0.178

Authors:

A.Y.Kovalevsky,Y.-F.Wang,Y.Tie,I.T.Weber

Key ref:

Y.Tie et al. (2007). Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir. Proteins, 67, 232-242. PubMed id: 17243183 DOI: 10.1002/prot.21304

Date:

21-Sep-10 Release date: 10-Nov-10

Supersedes:

2nmw

Protein chains

Q7SSI0  (Q7SSI0_9HIV1) -  Protease (Fragment) from Human immunodeficiency virus 1

Seq: 99 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.23.16 - HIV-1 retropepsin.
• Reaction: Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.

DOI no: 10.1002/prot.21304

Proteins 67:232-242 (2007)

PubMed id: 17243183

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

Y.Tie, A.Y.Kovalevsky, P.Boross, Y.F.Wang, A.K.Ghosh, J.Tozser, R.W.Harrison, I.T.Weber.

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 PR(I) (84V) and PR(V) (82A) containing the single mutations I84V and V82A that provide resistance to all the clinical inhibitors. Atomic resolution crystal structures (0.97-1.25 A) 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. PR(I) (84V) and PR(V) (82A) complexes were obtained in both the space groups P2(1)2(1)2 and P2(1)2(1)2(1), 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.

Selected figure(s)

Figure 1.
Figure 1. The 2F[o] - F[c] electron density map for the crystal structure of PR[V82A]/SQV. The major conformation is colored by atom type and the minor one is in magenta. (A) Saquinavir (contoured at 2.2 level). (B) Residues 79-82 (contoured at 1.8 level). (C) Catalytic site (contoured at 1.8 level). Asp25 and 25 are shown with the hydroxyl group of SQV.

Figure 3.
Figure 3. Hydrogen bond interactions between PR and inhibitor. Hydrogen bond interactions are indicated by dashed lines. Interactions mediated by water are shown in red. (A) Hydrogen bond interactions between PR and SQV. (B) Hydrogen bond interactions between PR and darunavir.

The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2007, 67, 232-242) copyright 2007.

Figures were selected by an automated process.