Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors

We report the structure of HIV-1 reverse transcriptase (RT) complexed with the nonnucleoside inhibitor TIBO R 86183 at 3.0 Å resolution. Comparing this structure with those of complexes of HIV-1 RT/α-APA R 95845 and HIV-1 RT/nevirapine provides a basis for understanding the nature of nonnucleoside inhibitor binding, the structure of the binding site and the interactions between the bound inhibitors and surrounding amino acid residues as well as for understanding mechanisms of inhibition by and resistance to nonnucleoside inhibitors. All three inhibitors considered assume a similar butterfly-like shape and bind to HIV-1 RT in a very similar way. Important differences occur in the conformation of amino acid residues that form the binding pocket.

[1]  T. Steitz,et al.  Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. , 1992, Science.

[2]  T. Steitz,et al.  Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[3]  L. Resnick,et al.  Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[4]  E. Clercq.  HIV resistance to reverse transcriptase inhibitors , 1994 .

[5]  W. Schleif,et al.  Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[6]  G J Kleywegt,et al.  Detection, delineation, measurement and display of cavities in macromolecular structures. , 1994, Acta crystallographica. Section D, Biological crystallography.

[7]  A. D. Clark,et al.  Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Jianping Ding,et al.  Review of HIV-1 reverse transcriptase three-dimensional structure : implications for drug design , 1993 .

[9]  Steven D. Young,et al.  Non-nucleoside inhibitors of HIV-1 reverse transcriptase , 1993 .

[10]  S. Hughes,et al.  Structures of DNA and RNA polymerases and their interactions with nucleic acid substrates. , 1995, Current opinion in structural biology.

[11]  P. Darke,et al.  L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. , 1994, Journal of medicinal chemistry.

[12]  D. Stuart,et al.  High resolution structures of HIV-1 RT from four RT-inhibitor complexes. , 1996 .

[13]  Erik De Clercq,et al.  HIV‐1‐specific RT inhibitors: Highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase , 1993, Medicinal research reviews.

[14]  J. Proudfoot,et al.  A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site. , 1991, Biochemistry.

[15]  R. Pauwels,et al.  A TIBO derivative, R82913, is a potent inhibitor of HIV-1 reverse transcriptase with heteropolymer templates. , 1991, Antiviral research.

[16]  A. Wlodawer,et al.  Structure-based inhibitors of HIV-1 protease. , 1993, Annual review of biochemistry.

[17]  B. Larder.  11 Inhibitors of HIV Reverse Transcriptase as Antiviral Agents and Drug Resistance , 1993 .

[18]  S. L. Le Grice,et al.  Mutating the "primer grip" of p66 HIV-1 reverse transcriptase implicates tryptophan-229 in template-primer utilization. , 1994, The Journal of biological chemistry.

[19]  Erik De Clercq,et al.  Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives , 1990, Nature.

[20]  Yvonne Jones,et al.  Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors , 1995, Nature Structural Biology.

[21]  A. D. Clark,et al.  Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 å resolution , 1995 .

[22]  T. Steitz,et al.  Comparison of three different crystal forms shows HIV-1 reverse transcriptase displays an internal swivel motion. , 1994, Structure.

[23]  R. Pauwels,et al.  Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of alpha-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[24]  PatrickY.-S. Lam,et al.  Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. , 1994, Science.

[25]  K A Johnson,et al.  Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors , 1995, Science.

[26]  J. Chou,et al.  Steady-state kinetic studies with the non-nucleoside HIV-1 reverse transcriptase inhibitor U-87201E. , 1993, The Journal of biological chemistry.

[27]  D W Rodgers,et al.  The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[28]  J. Condra,et al.  Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors , 1992, Antimicrobial Agents and Chemotherapy.

[29]  Jianping Ding,et al.  Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. , 1994, Journal of molecular biology.

[30]  E. De Clercq,et al.  New tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2',3'-dideoxynucleoside analogs , 1994, Antimicrobial Agents and Chemotherapy.

[31]  J. Adams,et al.  Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. , 1990, Science.

[32]  Mike Carson,et al.  Ribbon models of macromolecules , 1987 .

[33]  K. Frank,et al.  Kinetic interaction of human immunodeficiency virus type 1 reverse transcriptase with the antiviral tetrahydroimidazo[4,5,1-jk]-[1,4]-benzodiazepine-2-(1H)-thione compound, R82150. , 1991, The Journal of biological chemistry.