PDBsum entry 6fiv

Hydrolase/hydrolase inhibitor

PDB id: 6fiv

Contents

Protein chain

112 a.a. *

Ligands

SO4

3TL

Waters ×76

* Residue conservation analysis

PDB id:

6fiv

Name:

Hydrolase/hydrolase inhibitor

Title:

Structural studies of HIV and fiv proteases complexed with an efficient inhibitor of fiv pr

Structure:

Retropepsin. Chain: a. Engineered: yes. Other_details: complexed with tl-3-093

Source:

Feline immunodeficiency virus. Organism_taxid: 11674. Strain: (isolate petaluma). Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PQS)

Resolution:

1.90Å R-factor: 0.155 R-free: 0.266

Authors:

M.Li,T.Lee,G.Morris,G.Laco,C.Wong,A.Olson,J.Elder,A.Wlodawer, A.Gustchina

Key ref:

M.Li et al. (2000). Structural studies of FIV and HIV-1 proteases complexed with an efficient inhibitor of FIV protease. Proteins, 38, 29-40. PubMed id: 10651036 DOI: 10.1002/(SICI)1097-0134(20000101)38:1<29::AID-PROT4>3.0.CO;2-N

Date:

02-Dec-98 Release date: 09-Dec-98

Protein chain

P16088  (POL_FIVPE) -  Pol polyprotein from Feline immunodeficiency virus (isolate Petaluma)

Seq: 1124 a.a.

Struc: 112 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: E.C.2.7.7.- - ?????
• Enzyme class 3: E.C.2.7.7.49 - RNA-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.- - ?????
• Enzyme class 8: E.C.3.6.1.23 - dUTP diphosphatase.
• Reaction: dUTP + H2O = dUMP + diphosphate + H⁺

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: 10.1002/(SICI)1097-0134(20000101)38:1<29::AID-PROT4>3.0.CO;2-N

Proteins 38:29-40 (2000)

PubMed id: 10651036

Structural studies of FIV and HIV-1 proteases complexed with an efficient inhibitor of FIV protease.

M.Li, G.M.Morris, T.Lee, G.S.Laco, C.H.Wong, A.J.Olson, J.H.Elder, A.Wlodawer, A.Gustchina.

ABSTRACT

Three forms of feline immunodeficiency virus protease (FIV PR), the wild type (wt) and two single point mutants, V59I and Q99V, as well as human immunodeficiency virus type 1 protease (HIV-1 PR), were cocrystallized with the C2-symmetric inhibitor, TL-3. The mutants of FIV PR were designed to replace residues involved in enzyme-ligand interactions by the corresponding HIV-1 PR residues at the structurally equivalent position. TL-3 shows decreased (improved) inhibition constants with these FIV PR mutants relative to wt FIV PR. Despite similar modes of binding of the inhibitor to all PRs (from P3 to P3'), small differences are evident in the conformation of the Phe side chains of TL-3 at the P1 and P1' positions in the complexes with the mutated FIV PRs. The differences mimick the observed binding of TL-3 in HIV-1 PR and correlate with a significant improvement in the inhibition constants of TL-3 with the two mutant FIV PRs. Large differences between the HIV-1 and FIV PR complexes are evident in the binding modes of the carboxybenzyl groups of TL-3 at P4 and P4'. In HIV-1 PR:TL-3, these groups bind over the flap region, whereas in the FIV PR complexes, the rings are located along the major axis of the active site. A significant difference in the location of the flaps in this region of the HIV-1 and FIV PRs correlates with the observed conformational changes in the binding mode of the peptidomimetic inhibitor at the P4 and P4' positions. These findings provide a structural explanation of the observed Ki values for TL-3 with the different PRs and will further assist in the development of improved inhibitors.

Selected figure(s)

Figure 4.
Figure 4. Superposition of the crystal structures of wt FIV PR (blue) and its two mutants, V59I (yellow) and Q99V (purple), complexed with TL-3, near the S1 binding site. Water molecules are shown as spheres, whereas hydrogen bonds are shown as dotted lines.

Figure 6.
Figure 6. Comparison of the interface between the flap region and loop 93-98 (76-81) in wt FIV PR (blue) and HIV-1 PR (pink).

The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2000, 38, 29-40) copyright 2000.

Figures were selected by an automated process.