PDBsum entry 1hef

Hydrolase/hydrolase inhibitor

PDB id: 1hef

Contents

Protein chain

99 a.a. *

Ligands

ALA-ALA-PJJ-VAL-VME

Waters ×23

* Residue conservation analysis

PDB id:

1hef

Name:

Hydrolase/hydrolase inhibitor

Title:

The crystal structures at 2.2 angstroms resolution of hydroxyethylene- based inhibitors bound to human immunodeficiency virus type 1 protease show that the inhibitors are present in two distinct orientations

Structure:

HIV-1 protease. Chain: e. Engineered: yes. Skf 108738 peptide inhibitor. Chain: i. Engineered: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes

Biol. unit:

Tetramer (from PQS)

Resolution:

2.20Å R-factor: 0.159

Authors:

K.Murthy,E.L.Winborne,M.D.Minnich,J.S.Culp,C.Debouck

Key ref:

K.H.Murthy et al. (1992). The crystal structures at 2.2-A resolution of hydroxyethylene-based inhibitors bound to human immunodeficiency virus type 1 protease show that the inhibitors are present in two distinct orientations. J Biol Chem, 267, 22770-22778. PubMed id: 1429626

Date:

21-Sep-92 Release date: 31-May-94

Protein chain

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.*

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

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

J Biol Chem 267:22770-22778 (1992)

PubMed id: 1429626

The crystal structures at 2.2-A resolution of hydroxyethylene-based inhibitors bound to human immunodeficiency virus type 1 protease show that the inhibitors are present in two distinct orientations.

K.H.Murthy, E.L.Winborne, M.D.Minnich, J.S.Culp, C.Debouck.

ABSTRACT

As part of a structure-based drug design program directed against enzyme targets in the human immunodeficiency virus (HIV), we have determined the three-dimensional structures of the HIV type 1 protease complexed with two hydroxyethylene-based inhibitors. The inhibitors (SKF 107457 and SKF 108738) are hexapeptide substrate analogues with the scissile bond being replaced by a hydroxyethylene isostere. The structures were determined using x-ray diffraction data to 2.2 A measured at the Cornell High Energy Synchrotron Source on hexagonal crystals of each of the complexes. The structures have been extensively refined using a reciprocal space least-squares method to conventional crystallographic R factors of 0.186 and 0.159, respectively. The protein structure differs from that in the unliganded state of the enzyme and is most similar to that of the structure of the other reported (Jaskolski, M., Tomasselli, A. G., Sawyer, T. K., Staples, D. G., Heinrikson, R. L., Schneider, J., Kent, S. B. H., and Wlodawer, A. (1990) Biochemistry 29, 5889-5907) hydroxyethylene-based inhibitor complex. Unlike in that structure, however, the inhibitors are observed, in the present crystal structures, in two equally abundant orientations that are a consequence of the homodimeric nature of the enzyme coupled with the asymmetric structures of the inhibitors. Although the differences between the two inhibitors used in the present study are confined to the P1' site, the van der Waals interactions made by the inhibitor atoms with the amino acid residues in the protein differ throughout the structures of the inhibitors.