PDBsum entry 2fxe

Hydrolase

PDB id: 2fxe

Contents

Protein chains

99 a.a. *

Ligands

SO4 ×3

ACT

DR7

GOL ×2

Waters ×225

* Residue conservation analysis

PDB id:

2fxe

Name:

Hydrolase

Title:

X-ray crystal structure of HIV-1 protease crm mutant complexed with atazanavir (bms-232632)

Structure:

Pol protein. Chain: a, b. Fragment: HIV-1 protease. Engineered: yes. Mutation: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: pol. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.80Å R-factor: 0.202 R-free: 0.202

Authors:

S.Sheriff,H.E.Klei

Key ref:

H.E.Klei et al. (2007). X-ray crystal structures of human immunodeficiency virus type 1 protease mutants complexed with atazanavir. J Virol, 81, 9525-9535. PubMed id: 17537865

Date:

05-Feb-06 Release date: 20-Feb-07

Protein chains

P05959  (POL_HV1RH) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate RF/HAT3)

Seq: 1436 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.49 - RNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 2: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 3: 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 4: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 5: 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 Virol 81:9525-9535 (2007)

PubMed id: 17537865

X-ray crystal structures of human immunodeficiency virus type 1 protease mutants complexed with atazanavir.

H.E.Klei, K.Kish, P.F.Lin, Q.Guo, J.Friborg, R.E.Rose, Y.Zhang, V.Goldfarb, D.R.Langley, M.Wittekind, S.Sheriff.

ABSTRACT

Atazanavir, which is marketed as REYATAZ, is the first human immunodeficiency virus type 1 (HIV-1) protease inhibitor approved for once-daily administration. As previously reported, atazanavir offers improved inhibitory profiles against several common variants of HIV-1 protease over those of the other peptidomimetic inhibitors currently on the market. This work describes the X-ray crystal structures of complexes of atazanavir with two HIV-1 protease variants, namely, (i) an enzyme optimized for resistance to autolysis and oxidation, referred to as the cleavage-resistant mutant (CRM); and (ii) the M46I/V82F/I84V/L90M mutant of the CRM enzyme, which is resistant to all approved HIV-1 protease inhibitors, referred to as the inhibitor-resistant mutant. In these two complexes, atazanavir adopts distinct bound conformations in response to the V82F substitution, which may explain why this substitution, at least in isolation, has yet to be selected in vitro or in the clinic. Because of its nearly symmetrical chemical structure, atazanavir is able to make several analogous contacts with each monomer of the biological dimer.