PDBsum entry 1dtt

Hydrolase/transferase

PDB id: 1dtt

Contents

Protein chains

541 a.a. *

412 a.a. *

Ligands

FTC

* Residue conservation analysis

PDB id:

1dtt

Name:

Hydrolase/transferase

Title:

Crystal structure of HIV-1 reverse transcriptase in complex with pett- 2 (pett130a94)

Structure:

HIV-1 rt a-chain. Chain: a. Fragment: p66. Engineered: yes. HIV-1 rt b-chain. Chain: b. Fragment: p51. Engineered: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Expressed in: bacteria. Expression_system_taxid: 2. Expression_system_taxid: 2

Biol. unit:

Dimer (from PQS)

Resolution:

3.00Å R-factor: 0.199 R-free: 0.276

Authors:

J.Ren,J.Diprose,J.Warren,R.M.Esnouf,L.E.Bird,S.Ikemizu,M.Slater, J.Milton,J.Balzarini,D.I.Stuart,D.K.Stammers

Key ref:

J.Ren et al. (2000). Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses. J Biol Chem, 275, 5633-5639. PubMed id: 10681546 DOI: 10.1074/jbc.275.8.5633

Date:

13-Jan-00 Release date: 02-Apr-00

Protein chain

P04585  (POL_HV1H2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)

Seq: 1435 a.a.

Struc: 541 a.a.*

Protein chain

P04585  (POL_HV1H2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)

Seq: 1435 a.a.

Struc: 412 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

DOI no: 10.1074/jbc.275.8.5633

J Biol Chem 275:5633-5639 (2000)

PubMed id: 10681546

Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses.

J.Ren, J.Diprose, J.Warren, R.M.Esnouf, L.E.Bird, S.Ikemizu, M.Slater, J.Milton, J.Balzarini, D.I.Stuart, D.K.Stammers.

ABSTRACT

Most non-nucleoside reverse transcriptase (RT) inhibitors are specific for HIV-1 RT and demonstrate minimal inhibition of HIV-2 RT. However, we report that members of the phenylethylthiazolylthiourea (PETT) series of non-nucleoside reverse transcriptase inhibitors showing high potency against HIV-1 RT have varying abilities to inhibit HIV-2 RT. Thus, PETT-1 inhibits HIV-1 RT with an IC(50) of 6 nM but shows only weak inhibition of HIV-2 RT, whereas PETT-2 retains similar potency against HIV-1 RT (IC(50) of 5 nM) and also inhibits HIV-2 RT (IC(50) of 2.2 microM). X-ray crystallographic structure determinations of PETT-1 and PETT-2 in complexes with HIV-1 RT reveal the compounds bind in an overall similar conformation albeit with some differences in their interactions with the protein. To investigate whether PETT-2 could be acting at a different site on HIV-2 RT (e.g. the dNTP or template primer binding site), we compared modes of inhibition for PETT-2 against HIV-1 and HIV-2 RT. PETT-2 was a noncompetitive inhibitor with respect to the dGTP substrate for both HIV-1 and HIV-2 RTs. PETT-2 was also a noncompetitive inhibitor with respect to a poly(rC).(dG) template primer for HIV-2 RT. These results are consistent with PETT-2 binding in corresponding pockets in both HIV-1 and HIV-2 RT with amino acid sequence differences in HIV-2 RT affecting the binding of PETT-2 compared with PETT-1.

Selected figure(s)

Figure 1.
Fig. 1. Simulated annealing omit electron density maps showing the bound inhibitors at the NNRTI pocket of HIV-1 RT. a, PETT-1; b, PETT-2. The maps are contoured at 4 .

Figure 4.
Fig. 4. . Schematic diagrams showing the intermolecular interactions between PETT inhibitors (in red) and the surrounding residues of HIV-1 RT for (a) PETT-1 and (b) PETT-2. Residues that contact the NNRTI with a minimum inter-atomic distance of 3.6 Å are shown in green, whereas other residues lining the binding pocket are shown in blue. The individual distances between the NNRTI and the protein atoms are shown as dashed lines (distances 3.3 Å in pink, 3.3 Å < distances 3.6 Å in light blue). Hydrogen bonds together with their distances are shown in black.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2000, 275, 5633-5639) copyright 2000.

Figures were selected by an automated process.