PDBsum entry 1eet

Viral protein, transferase

PDB id: 1eet

Contents

Protein chains

542 a.a. *

399 a.a. *

Ligands

BFU

Waters ×34

* Residue conservation analysis

PDB id:

1eet

Name:

Viral protein, transferase

Title:

HIV-1 reverse transcriptase in complex with the inhibitor msc204

Structure:

HIV-1 reverse transcriptase. Chain: a. Fragment: residues 1-557. Engineered: yes. Mutation: yes. HIV-1 reverse transcriptase. Chain: b. Fragment: residues 1001-1427. Engineered: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: bh10. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.73Å R-factor: 0.213 R-free: 0.271

Authors:

M.Hogberg,C.Sahlberg,P.Engelhardt,R.Noreen,J.Kangasmetsa, N.G.Johansson,B.Oberg,L.Vrang,H.Zhang,B.L.Sahlberg,T.Unge,S.Lovgren, K.Fridborg,K.Backbro

Key ref:

M.Högberg et al. (1999). Urea-PETT compounds as a new class of HIV-1 reverse transcriptase inhibitors. 3. Synthesis and further structure-activity relationship studies of PETT analogues. J Med Chem, 42, 4150-4160. PubMed id: 10514285

Date:

03-Feb-00 Release date: 07-Feb-01

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: 542 a.a.*

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: 399 a.a.

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

Enzyme reactions

• Enzyme class 1: Chains A, B: E.C.2.7.7.- - ?????
• Enzyme class 2: Chains A, B: 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: Chains A, B: 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: Chains A, B: E.C.3.1.-.-
• Enzyme class 5: Chains A, B: 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: Chains A, B: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 7: Chains A, B: 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 Med Chem 42:4150-4160 (1999)

PubMed id: 10514285

Urea-PETT compounds as a new class of HIV-1 reverse transcriptase inhibitors. 3. Synthesis and further structure-activity relationship studies of PETT analogues.

M.Högberg, C.Sahlberg, P.Engelhardt, R.Noréen, J.Kangasmetsä, N.G.Johansson, B.Oberg, L.Vrang, H.Zhang, B.L.Sahlberg, T.Unge, S.Lövgren, K.Fridborg, K.Bäckbro.

ABSTRACT

The further development of allosteric HIV-1 RT inhibitors in the urea analogue series of PETT (phenylethylthiazolylthiourea) derivatives is described here. The series includes derivatives with an ethyl linker (1-5) and racemic (6-16) and enantiomeric (17-20) cis-cyclopropane compounds. The antiviral activity was determined both at the RT level and in cell culture on both wild-type and mutant forms of HIV-1. Most compounds have anti-HIV-1 activity on the wt in the nanomolar range. Resistant HIV-1 was selected in vitro for some of the compounds, and the time for resistant HIV-1 to develop was longer for urea-PETT compounds than it was for reference compounds. Preliminary pharmacokinetics in rats showed that compound 18 is orally bioavailable and penetrates well into the brain. The three-dimensional structure of complexes between HIV-1 RT and two enantiomeric compounds (17 and 18) have been determined. The structures show similar binding in the NNI binding pocket. The propionylphenyl moieties of both inhibitors show perfect stacking to tyrosine residues 181 and 188. The cyclopropyl moiety of the (+)-enantiomer 18 exhibits optimal packing distances for the interactions with leucine residue 100 and valine residue 179.