Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors
作者： Robert Esnouf , Jingshan Ren , Carl Ross , Yvonne Jones , David Stammers
DOI: 10.1038/NSB0495-303
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摘要: The structure of unliganded HIV-1 reverse transcriptase has been determined at 2.35 A resolution and refined to an R-factor 0.219 (for all data) with good stereochemistry. was produced by soaking out a weak binding non-nucleoside inhibitor, HEPT, from pregrown crystals. Comparison the structures four different RT inhibitor complexes reveals that only minor domain rearrangements occur, but there is significant repositioning three-stranded beta-sheet in p66 subunit (containing catalytic aspartic acid residues 110, 185 186) respect rest polymerase site. This suggests NNIs inhibit locking active site inactive conformation, reminiscent conformation observed p51 subunit.
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Chris Tantillo, Jianping Ding, Alfredo Jacobo-Molina, Raymond G. Nanni, Paul L. Boyer, Stephen H. Hughes, Rudi Pauwels, Koen Andries, Paul A.J. Janssen, Edward Arnold, 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 Journal of Molecular Biology. ,vol. 243, pp. 369- 387 ,(1994) , 10.1006/JMBI.1994.1665
Y. Engelborghs, Z. Debyser, K. Andries, P. A. J. Janssen, E. De Clercq, J. Desmyter, R. Pauwels, Allosteric inhibition of human immunodeficiency virus type 1 reverse transcriptase by tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione compounds. Molecular Pharmacology. ,vol. 41, pp. 203- 208 ,(1992)
G. Divita, B. Mueller, U. Immendoerfer, M. Gautel, K. Rittinger, T. Restle, R. S. Goody, Kinetics of interaction of HIV reverse transcriptase with primer/template Biochemistry. ,vol. 32, pp. 7966- 7971 ,(1993) , 10.1021/BI00082A018
Joe C. Wu, Thomas C. Warren, Julian Adams, John Proudfoot, Jerry Skiles, Palayakotai Raghavan, Clark Perry, Ian Potocki, Peter R. Farina, Peter M. Grob, A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site. Biochemistry. ,vol. 30, pp. 2022- 2026 ,(1991) , 10.1021/BI00222A003
Noriyoshi Sakabe, None, X-ray diffraction data collection system for modern protein crystallography with a Weissenberg camera and an imaging plate using synchrotron radiation Nuclear Instruments & Methods in Physics Research Section A-accelerators Spectrometers Detectors and Associated Equipment. ,vol. 303, pp. 448- 463 ,(1991) , 10.1016/0168-9002(91)90282-U
Z. Debyser, R. Pauwels, K. Andries, J. Desmyter, M. Kukla, P. A. Janssen, E. De Clercq, An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk] [1,4]benzodiazepin-2 (1H)-one and -thione derivatives. Proceedings of the National Academy of Sciences of the United States of America. ,vol. 88, pp. 1451- 1455 ,(1991) , 10.1073/PNAS.88.4.1451
L. Kohlstaedt, J Wang, J. Friedman, P. Rice, T. Steitz, Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. ,vol. 256, pp. 1783- 1790 ,(1992) , 10.1126/SCIENCE.1377403
T. A. Jones, J. Y. Zou, S. W. Cowan, M. Kjeldgaard, Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallographica Section A. ,vol. 47, pp. 110- 119 ,(1991) , 10.1107/S0108767390010224
M. Baba, H. Tanaka, E. De Clercq, R. Pauwels, J. Balzarini, D. Schols, H. Nakashima, C.-F. Perno, R.T. Walker, T. Miyasaka, Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative Biochemical and Biophysical Research Communications. ,vol. 165, pp. 1375- 1381 ,(1989) , 10.1016/0006-291X(89)92756-3
P. J. Kraulis, MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures Journal of Applied Crystallography. ,vol. 24, pp. 946- 950 ,(1991) , 10.1107/S0021889891004399