Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 å resolution

J Ding; K Das; C Tantillo; W Zhang; A D Clark, Jr; S Jessen; X Lu; Y Hsiou; A Jacobo-Molina; K Andries; R Pauwels; H Moereels; L Koymans; PAJ Janssen; R H Smith, Jr; M.Kroeger Koepke; C J Michejda; S H Hughes; E Arnold

doi:10.1016/S0969-2126(01)00168-X

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Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 å resolution

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Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 å resolution

J Ding, K Das, C Tantillo, W Zhang, A D Clark, Jr, S Jessen, X Lu, Y Hsiou, A Jacobo-Molina, K Andries, …

Structure (London), Vol.3(4), pp.365-379

1995

DOI: https://doi.org/10.1016/S0969-2126(01)00168-X

PMID: 7542140

Abstract

protein-drug interactions

mechanism of non-nucleoside

polymerase structure

AIDS

Drug Resistance

Background: HIV-1 reverse transcriptase (RT) is a multifunctional enzyme that copies the RNA genome of HIV-1 into DNA. It is a heterodimer composed of a 66 kDa (p66) and a 51 kDa (p51) subunit. HIV-1 RT is a crucial target for structure-based drug design, and potent inhibitors have been identified, whose efficacy, however, is limited by drug resistance. Results The crystal structure of HIV-1 RT in complex with the non-nucleoside inhibitor α-anilinophenylacetamide ( α-APA) R 95845 has been determined at 2.8 å resolution. The inhibitor binds in a hydrophobic pocket near the polymerase active site. The pocket contains five aromatic amino acid residues and the interactions of the side chains of these residues with the aromatic rings of non-nucleoside inhibitors appear to be important for inhibitor binding. Most of the amino acid residues where mutations have been correlated with high levels of resistance to non-nucleoside inhibitors of HIV-1 RT are located close to α-APA. The overall fold of HIV-1 RT in complex with α-APA is similar to that found when in complex with nevirapine, another non-nucleoside inhibitor, but there are significant conformational changes relative to an HIV-1 RT/DNA/Fab complex. Conclusion The non-nucleoside inhibitor-binding pocket has a flexible structure whose mobility may be required for effective polymerization, and may be part of a hinge that permits relative movements of two subdomains of the p66 subunit denoted the ‘palm’ and ‘thumb’. An understanding of the structure of the inhibitor-binding pocket, of the interactions between HIV-1 RT and α-APA, and of the locations of mutations that confer resistance to inhibitors provides a basis for structure-based design of chemotherapeutic agents for the treatment of AIDS.

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Title: Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 å resolution
Creators: J Ding - J Ding, C Tantillo, W Zhang, AD Clark, Jr, S Jessen, X Lu, Y Hsiou, A Jacobo-Molina and E Arnold (corresponding author), Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemisty Department, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA
K Das - K Andries, H Moereels, L Koymans and PAJ Janssen, Janssen Research Foundation, Turnhoutseweg 30, B-2340, Beerse, Belgium
C Tantillo - J Ding, C Tantillo, W Zhang, AD Clark, Jr, S Jessen, X Lu, Y Hsiou, A Jacobo-Molina and E Arnold (corresponding author), Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemisty Department, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA
W Zhang - J Ding, C Tantillo, W Zhang, AD Clark, Jr, S Jessen, X Lu, Y Hsiou, A Jacobo-Molina and E Arnold (corresponding author), Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemisty Department, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA
A D Clark, Jr - J Ding, C Tantillo, W Zhang, AD Clark, Jr, S Jessen, X Lu, Y Hsiou, A Jacobo-Molina and E Arnold (corresponding author), Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemisty Department, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA
S Jessen - J Ding, C Tantillo, W Zhang, AD Clark, Jr, S Jessen, X Lu, Y Hsiou, A Jacobo-Molina and E Arnold (corresponding author), Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemisty Department, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA
X Lu - J Ding, C Tantillo, W Zhang, AD Clark, Jr, S Jessen, X Lu, Y Hsiou, A Jacobo-Molina and E Arnold (corresponding author), Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemisty Department, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA
Y Hsiou - J Ding, C Tantillo, W Zhang, AD Clark, Jr, S Jessen, X Lu, Y Hsiou, A Jacobo-Molina and E Arnold (corresponding author), Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemisty Department, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA
A Jacobo-Molina - J Ding, C Tantillo, W Zhang, AD Clark, Jr, S Jessen, X Lu, Y Hsiou, A Jacobo-Molina and E Arnold (corresponding author), Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemisty Department, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA
K Andries - K Andries, H Moereels, L Koymans and PAJ Janssen, Janssen Research Foundation, Turnhoutseweg 30, B-2340, Beerse, Belgium
R Pauwels - R Pauwels, TIBOTEC, Institute for Antiviral Research, Drie Eikenstraat 661, B-2650, Edegem, Belgium
H Moereels - K Andries, H Moereels, L Koymans and PAJ Janssen, Janssen Research Foundation, Turnhoutseweg 30, B-2340, Beerse, Belgium
L Koymans - K Andries, H Moereels, L Koymans and PAJ Janssen, Janssen Research Foundation, Turnhoutseweg 30, B-2340, Beerse, Belgium
PAJ Janssen - K Andries, H Moereels, L Koymans and PAJ Janssen, Janssen Research Foundation, Turnhoutseweg 30, B-2340, Beerse, Belgium
R H Smith, Jr - RH Smith, Jr, M Kroeger Koepke, CJ Michejda and SH Hughes, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, P.O. Box B, Frederick, MD 21702-1201, USA
M.Kroeger Koepke - RH Smith, Jr, M Kroeger Koepke, CJ Michejda and SH Hughes, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, P.O. Box B, Frederick, MD 21702-1201, USA
C J Michejda - RH Smith, Jr, M Kroeger Koepke, CJ Michejda and SH Hughes, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, P.O. Box B, Frederick, MD 21702-1201, USA
S H Hughes - RH Smith, Jr, M Kroeger Koepke, CJ Michejda and SH Hughes, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, P.O. Box B, Frederick, MD 21702-1201, USA
E Arnold - J Ding, C Tantillo, W Zhang, AD Clark, Jr, S Jessen, X Lu, Y Hsiou, A Jacobo-Molina and E Arnold (corresponding author), Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemisty Department, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA
Publication Details: Structure (London), Vol.3(4), pp.365-379
Date published: 1995
Publisher: Elsevier Inc
Academic Unit: Center for Advanced Biotechnology and Medicine
Language: English
Resource Type: Journal article
Identifiers: 991031653870404646