PDBsum entry 1d4h

Hydrolase

PDB id: 1d4h

Contents

Protein chains

99 a.a. *

Ligands

BEH

Waters ×129

* Residue conservation analysis

PDB id:

1d4h

Name:

Hydrolase

Title:

HIV-1 protease in complex with the inhibitor bea435

Structure:

HIV-1 protease. Chain: a, b. Engineered: yes

Source:

Human immunodeficiency virus. Organism_taxid: 12721. Strain: bh10. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

1.81Å R-factor: 0.195 R-free: 0.231

Authors:

T.Unge

Key ref:

H.O.Andersson et al. (2003). Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors. Eur J Biochem, 270, 1746-1758. PubMed id: 12694187 DOI: 10.1046/j.1432-1033.2003.03533.x

Date:

04-Oct-99 Release date: 26-Jun-02

Protein chains

P03366  (POL_HV1B1) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BH10)

Seq: 1447 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.3.4.23.16 - HIV-1 retropepsin.
• Reaction: Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.

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: 10.1046/j.1432-1033.2003.03533.x

Eur J Biochem 270:1746-1758 (2003)

PubMed id: 12694187

Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors.

H.O.Andersson, K.Fridborg, S.Löwgren, M.Alterman, A.Mühlman, M.Björsne, N.Garg, I.Kvarnström, W.Schaal, B.Classon, A.Karlén, U.H.Danielsson, G.Ahlsén, U.Nillroth, L.Vrang, B.Oberg, B.Samuelsson, A.Hallberg, T.Unge.

ABSTRACT

HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 A resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the delta-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.

Selected figure(s)

Figure 1.
Fig. 1. Orientation of the inhibitor in the active site and arrangement of the central vicinal hydroxyls (stereo view). The figure shows the structure of the asymmetric compound 3 as it is arranged in the HIV-1 protease active site. The electron density map indicates a unique orientation of the inhibitor and the whole protease–inhibitor complex in the crystal lattice. The density also indicates an 90% unique orientation of the central vicinal hydroxy groups in the complex with this compound. The Fo–Fc electron density map was calculated at 2.0 Å resolution with the inhibitor compound omitted, and contoured at 2.5 .

Figure 2.
Fig. 2. Positioning of the inhibitor in the active site and hydrogen-bond network. One of the inhibitor hydroxyls has extensive contacts with the catalytic Asp25/Asp125. The hydrogen-bond distances are short (2.7–2.8 Å). The gauche hydroxy group is hydrogen-bonded to one of the catalytic aspartate residues. Gly27/Gly127 contribute to the active-site hydrogen-bond network by donation of hydrogens via the main-chain amide groups. These two compounds 1 and 2 represent the two groups of inhibitors in this study. Compound 1 (A) has 10 and compound 2 (B) has 8 hydrogen-bond donors/acceptors. In the latter case, two water molecules remain co-ordinated to the G48/G148 carbonyl groups after complex formation.

The above figures are reprinted by permission from the Federation of European Biochemical Societies: Eur J Biochem (2003, 270, 1746-1758) copyright 2003.

Figures were selected by an automated process.