PDBsum entry 3ecg

Hydrolase

PDB id: 3ecg

Contents

Protein chains

99 a.a. *

Ligands

065

IMD ×6

Metals

_NA

_CL ×9

_ZN ×11

Waters ×203

* Residue conservation analysis

PDB id:

3ecg

Name:

Hydrolase

Title:

High resolution HIV-2 protease structure in complex with antiviral inhibitor grl-98065

Structure:

Protease. Chain: a, b. Engineered: yes

Source:

Human immunodeficiency virus type 2 (isolate rod). Organism_taxid: 11720. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.18Å R-factor: 0.145 R-free: 0.188

Authors:

A.Y.Kovalevsky,I.T.Weber

Key ref:

A.Y.Kovalevsky et al. (2008). Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease. J Mol Biol, 384, 178-192. PubMed id: 18834890 DOI: 10.1016/j.jmb.2008.09.031

Date:

29-Aug-08 Release date: 16-Sep-08

Protein chains

P04584  (POL_HV2RO) -  Gag-Pol polyprotein from Human immunodeficiency virus type 2 subtype A (isolate ROD)

Seq: 1464 a.a.

Struc: 99 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.- - ?????
• Enzyme class 2: E.C.2.7.7.49 - RNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 3: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 4: E.C.3.1.-.-
• Enzyme class 5: E.C.3.1.13.2 - exoribonuclease H.
• Reaction: Exonucleolytic cleavage to 5'-phosphomonoester oligonucleotides in both 5'- to 3'- and 3'- to 5'-directions.
• Enzyme class 6: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 7: E.C.3.4.23.47 - HIV-2 retropepsin.

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.jmb.2008.09.031

J Mol Biol 384:178-192 (2008)

PubMed id: 18834890

Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease.

A.Y.Kovalevsky, J.M.Louis, A.Aniana, A.K.Ghosh, I.T.Weber.

ABSTRACT

No drug has been targeted specifically for HIV-2 (human immunodeficiency virus type 2) infection despite its increasing prevalence worldwide. The antiviral HIV-1 (human immunodeficiency virus type 1) protease (PR) inhibitor darunavir and the chemically related GRL98065 and GRL06579A were designed with the same chemical scaffold and different substituents at P2 and P2' to optimize polar interactions for HIV-1 PR (PR1). These inhibitors are also effective antiviral agents for HIV-2-infected cells. Therefore, crystal structures of HIV-2 PR (PR2) complexes with the three inhibitors have been solved at 1.2-A resolution to analyze the molecular basis for their antiviral potency. Unusually, the crystals were grown in imidazole and zinc acetate buffer, which formed interactions with the PR2 and the inhibitors. Overall, the structures were very similar to the corresponding inhibitor complexes of PR1 with an RMSD of 1.1 A on main-chain atoms. Most hydrogen-bond and weaker C-H...O interactions with inhibitors were conserved in the PR2 and PR1 complexes, except for small changes in interactions with water or disordered side chains. Small differences were observed in the hydrophobic contacts for the darunavir complexes, in agreement with relative inhibition of the two PRs. These near-atomic-resolution crystal structures verify the inhibitor potency for PR1 and PR2 and will provide the basis for the development of antiviral inhibitors targeting PR2.

Selected figure(s)

Figure 5.
Fig. 5. Polar interactions between PR2 and inhibitors (a) DRV, (b) GRL06579A, and (c) GRL98065. Hydrogen bonds are indicated by dashed lines. The alternate conformation of the Asp30 side chain in PR2–GRL06579A is shown in magenta. The two shortest distances connecting the central OH group of each inhibitor with the catalytic Asp25 and 25′ are indicated by green dotted lines. The O–H…π interaction between the aromatic system of P2 group and a water molecule is indicated by a black dotted line.

Figure 7.
Fig. 7. Schematic representation of C–H…O unconventional hydrogen-bond interactions in (a) PR2–DRV, (b) PR2–GRL06579A, and (c) PR2–GRL98065. Pink dotted lines indicate C–H…O contacts with distances in angstrom. The green dotted lines indicate the O–H…O hydrogen bonds of the catalytic Asp25/Asp25′.

The above figures are reprinted from an Open Access publication published by Elsevier: J Mol Biol (2008, 384, 178-192) copyright 2008.

Figures were selected by the author.

Author's comment

The crystal structures of HIV-2 protease with antiviral inhibitors suggest that darunavir and related inhibitors will be effective on both HIV-2 and HIV-1 infections.