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J Biol Chem, Vol. 275, Issue 19, 14316-14320, May 12, 2000
From the S-1153 (AG1549) is perhaps the most promising
non-nucleoside inhibitor of HIV-1 reverse transcriptase currently under
development as a potential anti-AIDS drug, because it has a favorable
profile of resilience to many drug resistance mutations. We have
determined the crystal structure of S-1153 in a complex with HIV-1
reverse transcriptase. The complex possesses some novel features,
including an extensive network of hydrogen bonds involving the main
chain of residues 101, 103, and 236 of the p66 reverse transcriptase subunit. Such interactions are unlikely to be disrupted by side chain
mutations. The reverse transcriptase/S-1153 complex suggests different
ways in which resilience to mutations in the non-nucleoside inhibitors
of reverse transcriptase binding site can be
achieved.
The atomic coordinates and structure factors (codes 1ep4 and 1ep4sf ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
Binding of the Second Generation Non-nucleoside
Inhibitor S-1153 to HIV-1 Reverse Transcriptase Involves Extensive
Main Chain Hydrogen Bonding*
,,,¶
, and¶
Structural Biology Division, The Wellcome
Trust Centre for Human Genetics, University of Oxford, Roosevelt
Drive, Oxford, OX3 7BN, United Kingdom, § Discovery
Research Laboratories, Shionogi & Co. Ltd., 5-12-4 Sagisu
Fukushima-ku, Osaka 553-0002, Japan, and the ¶ Oxford Centre for
Molecular Sciences, New Chemistry Building, South Parks Road,
Oxford, OX1 3QT, United Kingdom
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Scheme 1.
*
The Oxford Centre for Molecular Sciences is supported by the
Biotechnology and Biological Sciences Research Council, the Medical Research Council, and the Engineering and Physical Sciences Research Council.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by the Medical Research Council. The AIDS-directed
program of the Medical Research Council has provided long term funding
for the work at Oxford with grants to these authors. To whom
correspondence may be addressed: Tel.: 44-1865-287-565 and 44-1865-287-567; Fax: 44-1865-287-547; E-mail: daves@strubi.ox.ac.uk (D. K. S.) and dave@strubi.ox.ac.uk (D. I. S.).
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