1TV6

HIV-1 Reverse Transcriptase Complexed with CP-94,707

Summary for 1TV6

• Entry DOI: 10.2210/pdb1tv6/pdb
• Related: 3HVT
• Descriptor: reverse transcriptase p66 subunit, reverse transcriptase p51 subunit, 3-[4-(2-METHYL-IMIDAZO[4,5-C]PYRIDIN-1-YL)BENZYL]-3H-BENZOTHIAZOL-2-ONE (3 entities in total)
• Functional Keywords: transferase
• Biological source: Human immunodeficiency virus type 1 BH10; More
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03366 P03366
• Total number of polymer chains: 2
• Total formula weight: 116260.51

Authors

Pata, J.D.,Stirtan, W.G.,Goldstein, S.W.,Steitz, T.A. (deposition date: 2004-06-28, release date: 2004-07-20, Last modification date: 2023-08-23)

Primary citation

Pata, J.D.,Stirtan, W.G.,Goldstein, S.W.,Steitz, T.A.
Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant RTs resistant to other non-nucleoside inhibitors
Proc.Natl.Acad.Sci.USA, 101:10548-10553, 2004

PubMed Abstract: We have determined the crystal structure of the HIV type 1 reverse transcriptase complexed with CP-94,707, a new nonnucleoside reverse transcriptase inhibitor (NNRTI), to 2.8-A resolution. In addition to inhibiting the wild-type enzyme, this compound inhibits mutant enzymes that are resistant to inhibition by nevirapine, efavirenz, and delaviridine. In contrast to other NNRTI complexes where tyrosines 181 and 188 are pointing toward the enzyme active site, the binding pocket in this complex has the tyrosines pointing the opposite direction, as in the unliganded protein structure, to accommodate CP-94,707. This conformation of the pocket has not been observed previously in NNRTI complexes and substantially alters the shape and surface features that are available for interactions with the inhibitor. One ring of CP-94,707 makes extensive stacking interactions with tryptophan 229, one of the few residues in the NNRTI-binding pocket that cannot readily mutate to give rise to drug resistance. In this conformation of the pocket, mutations of tyrosines 181 and 188 are less likely to disrupt inhibitor binding. Modeling the asparagine mutation of lysine 103 shows that a hydrogen bond between it and tyrosine 188 could form as readily in the CP-94,707 complex as it does in the apoenzyme structure, providing an explanation for the activity of this inhibitor against this clinically important mutant.

PubMed: 15249669
DOI: 10.1073/pnas.0404151101

Experimental method

X-RAY DIFFRACTION (2.8 Å)