PDBsum entry 1idb

Hydrolase/hydrolase inhibitor

PDB id: 1idb

Contents

Protein chains

99 a.a. *

Ligands

0DO

Waters ×42

* Residue conservation analysis

PDB id:

1idb

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structures of HIV-2 protease in complex with inhibitors containing the hydroxyethylamine dipeptide isostere

Structure:

Protease. Chain: a, b. Engineered: yes

Source:

Human immunodeficiency virus 2. Organism_taxid: 11709. Gene: pol. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Trimer (from PQS)

Resolution:

2.20Å R-factor: 0.180

Authors:

L.Tong,P.C.Anderson

Key ref:

L.Tong et al. (1995). Crystal structures of HIV-2 protease in complex with inhibitors containing the hydroxyethylamine dipeptide isostere. Structure, 3, 33-40. PubMed id: 7743130 DOI: 10.1016/S0969-2126(01)00133-2

Date:

19-Oct-94 Release date: 26-Jan-95

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/S0969-2126(01)00133-2

Structure 3:33-40 (1995)

PubMed id: 7743130

Crystal structures of HIV-2 protease in complex with inhibitors containing the hydroxyethylamine dipeptide isostere.

L.Tong, S.Pav, S.Mui, D.Lamarre, C.Yoakim, P.Beaulieu, P.C.Anderson.

ABSTRACT

BACKGROUND: The HIV protease is essential for the life cycle of the virus and is an important target for the development of therapeutic treatments against AIDS. The structures of HIV protease in complex with different inhibitors have helped in understanding the interactions between inhibitors and the protease and in the design and optimization of HIV protease inhibitors. RESULTS: We report here crystal structures at up to 1.7 A resolution of the homodimeric HIV-2 protease in complex with seven inhibitors containing the hydroxyethylamine dipeptide isostere. A novel dimethylphenoxyacetyl group that is present in some of these inhibitors is inserted between residues 48' and 49' in the flap of the protease and residues 29' and 30' (where a prime indicates a residue in the second monomer), which undergo a conformational change to accommodate the phenyl ring of the inhibitor. CONCLUSIONS: This study shows that besides the residues in the flap and residues 79-81 in the S1 substrate-binding pocket which undergo conformational changes upon inhibitor binding, residues 29 and 30 can also adapt their conformation to fit certain inhibitors. Conformational flexibility of the HIV protease plays an important role in inhibitor binding.

Selected figure(s)

Figure 5.
Figure 5. The binding modes of the inhibitors. (a) Overlap of the bound conformation of the long inhibitors 1 (red), 2 (cyan) and 3 (black). (b) Overlap of the bound conformation of the short inhibitors 4 (black), 5 (cyan), 6 (pink) and 7 (green). (c ) Overlap of the bound conformation of the long inhibitor 1 (red) and the short inhibitor 7 (green) . Figure 5. The binding modes of the inhibitors. (a) Overlap of the bound conformation of the long inhibitors 1 (red), 2 (cyan) and 3 (black). (b) Overlap of the bound conformation of the short inhibitors 4 (black), 5 (cyan), 6 (pink) and 7 (green). (c ) Overlap of the bound conformation of the long inhibitor 1 (red) and the short inhibitor 7 (green) .

Figure 6.
Figure 6. (a) Hydrogen-bonding interactions between inhibitor 1 and the protease. (b) The interactions between the hydroxyl of the isostere and the catalytic aspartic acid residues . Figure 6. (a) Hydrogen-bonding interactions between inhibitor 1 and the protease. (b) The interactions between the hydroxyl of the isostere and the catalytic aspartic acid residues .

The above figures are reprinted by permission from Cell Press: Structure (1995, 3, 33-40) copyright 1995.

Figures were selected by an automated process.