1RT2

CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE COMPLEXED WITH TNK-651

Summary for 1RT2

• Entry DOI: 10.2210/pdb1rt2/pdb
• Descriptor: HIV-1 REVERSE TRANSCRIPTASE, 6-BENZYL-1-BENZYLOXYMETHYL-5-ISOPROPYL URACIL, ... (4 entities in total)
• Functional Keywords: nucleotidyltransferase, hiv-1 reverse transcriptase
• 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: 116358.43

Authors

Ren, J.,Esnouf, R.,Hopkins, A.,Willcox, B.,Jones, Y.,Ross, C.,Stammers, D.,Stuart, D. (deposition date: 1996-03-16, release date: 1997-04-21, Last modification date: 2024-11-20)

Primary citation

Hopkins, A.L.,Ren, J.,Esnouf, R.M.,Willcox, B.E.,Jones, E.Y.,Ross, C.,Miyasaka, T.,Walker, R.T.,Tanaka, H.,Stammers, D.K.,Stuart, D.I.
Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors.
J.Med.Chem., 39:1589-1600, 1996

PubMed Abstract: Crystal structures of HIV-1 reverse transcriptase (RT) complexed with a range of chemically diverse non-nucleoside inhibitors (NNIs) have shown a single pocket in which the inhibitors bind and details of the inhibitor-protein interactions. To delineate the structural requirements for an effective inhibitor, we have determined the structures of three closely related NNIs which vary widely in their potencies. Crystal structures of HIV-1 RT complexed with two very potent inhibitors, MKC-442 and TNK-651, at 2.55 angstroms resolution complement our previous analysis of the complex with the less effective inhibitor, HEPT. These structures reveal conformational changes which correlate with changes in potency. We suggest that a major determinant of increased potency in the analogues of HEPT is an improved interaction between residue Tyr181 in the protein and the 6-benzyl ring of the inhibitors which stabilizes the structure of the complex. This arises through a conformational switching of the protein structure triggered by the steric bulk of the 5-substituent of the inhibitor pyrimidine ring.

PubMed: 8648598
DOI: 10.1021/jm960056x

Experimental method

X-RAY DIFFRACTION (2.55 Å)