1DTT

CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH PETT-2 (PETT130A94)

Summary for 1DTT

• Entry DOI: 10.2210/pdb1dtt/pdb
• Related: 1c0t 1c0u 1c1b 1c1c 1dtq 1klm 1rev 1rt1 1rt2 1rt3 1rt4 1rt5 1rt6 1rt7 1rth 1rti 1rtj 1rtv 1vru
• Descriptor: HIV-1 RT A-CHAIN, HIV-1 RT B-CHAIN, N-[[3-FLUORO-4-ETHOXY-PYRID-2-YL]ETHYL]-N'-[5-CHLORO-PYRIDYL]-THIOUREA (3 entities in total)
• Functional Keywords: hiv-1 reverse transcriptase aids, non-nucleoside inhibitor, drug design, hydrolase-transferase complex, hydrolase/transferase
• Biological source: Human immunodeficiency virus 1; More
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor . Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P04585 P04585
• Total number of polymer chains: 2
• Total formula weight: 116348.83

Authors

Ren, J.,Diprose, J.,Warren, J.,Esnouf, R.M.,Bird, L.E.,Ikemizu, S.,Slater, M.,Milton, J.,Balzarini, J.,Stuart, D.I.,Stammers, D.K. (deposition date: 2000-01-13, release date: 2000-04-02, Last modification date: 2024-11-13)

Primary citation

Ren, J.,Diprose, J.,Warren, J.,Esnouf, R.M.,Bird, L.E.,Ikemizu, S.,Slater, M.,Milton, J.,Balzarini, J.,Stuart, D.I.,Stammers, D.K.
Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses.
J.Biol.Chem., 275:5633-5639, 2000

PubMed 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.

PubMed: 10681546
DOI: 10.1074/jbc.275.8.5633

Experimental method

X-RAY DIFFRACTION (3 Å)