The conformation of a peptidyl methyl ketone inhibitor bound to the human cytomegalovirus protease

Angewandte Chemie - International Edition

Volumn 37, Issue 19, 1998, Pages 2729-2732

  LaPlante, Steven R ^a   Cameron, Dale R ^a   Aubry, Norman ^a   Bonneau, Pierre R ^a   Déziel, Robert ^a   Grand Maître, Chantal ^a   Ogilvie, William W ^a   Kawai, Stephen H ^a  

^a BOEHRINGER INGELHEIM CANADA LTD   (Canada)

Author keywords

Conformation analysis; Molecular modeling; NMR spectroscopy; Peptidomimetics

Indexed keywords

EID: 0032538482     PISSN: 14337851     EISSN: None     Source Type: Journal    
DOI: 10.1002/(SICI)1521-3773(19981016)37:19<2729::AID-ANIE2729>3.0.CO;2-4     Document Type: Article

References (29)

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10. X-ray crystallographic structures of apoenzyme: a) L. Tong, C. Qian, M.-J. Massariol, P. R. Bonneau, M. G. Cordingley, L. Lagacé, Nature 1996, 383, 272-275; b) X. Qiu, J. S. Culp, A. G. DiLella, B. Hellmig, S. S. Hoog, C. A. Janson, W. W. Smith, S. S. Abdel-Meguid, Nature 1996, 383, 275-279; c) H.-S. Shieh, R. G. Kurumball, A. M. Stevens, R. A. Stegeman, E. J. Sturman, J. Y. Pak, A. J. Wittwer, M. O. Palmier, R. C. Wiegand, B. C. Holwerda, W. C. Stallings, Nature 1996, 383, 279-282; d) P. Chen, H. Tsuge, R. J. Almassy, C. L. Gribskov, S. Katoh, D. L. Vanderpool, S. A. Margosiak, C. Pinko, D. A. Matthews, C.-C. Kan, Cell 1996, 86, 835-843.
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19. 2O resonance. The 2D NOESY experiments (J. Jeener, B. H. Meier, P. Bachmann, R. R. Ernst, J. Chem. Phys. 1979, 64, 4546-4553; S. Macura, R. R. Ernst, Mol. Phys. 1980, 41, 95-117) were carried out on a Varian UNITY instrument (750 MHz) equipped with pulse field gradient accessories. Samples consisted of 3.1 mM MK2 and 0.26 mM protease in the standard buffer at pH 7. Phase-sensitive spectra were acquired at 10°C using the time proportional phase incrementation (TPPI) method (D. Marion, K. Wüthrich, Biochem. Biophys. Res. Commun. 1983, 113, 967-974; A. G. Redfield, S. D. Kuntz, J. Magn. Res. 1975, 19, 250-254). Water suppression was achieved by inserting a 3-9-19 WATERGATE module prior to acquisition ( M. Piotto, V. Saudek, V. Sklenar, J. Biolmol. NMR 1992, 2, 661-665; V. Sklenar, M. Piotto, R. Lippek, V. Saudek, J. Magn. Reson. A 1993, 102, 241-245). The NOESY spectra were acquired using mixing times of 50, 100, 150, and 250 ms, and a selective flip-back pulse was employed just prior to the readout pulse to maintain the water magnetization along the positive z axis during acquisition and relaxation delay (G. Lippens, C. Dhalluin, C. Wieruszeski, J. Biomol. NMR 1995, 5, 327-331).
20. 2O resonance. The 2D NOESY experiments (J. Jeener, B. H. Meier, P. Bachmann, R. R. Ernst, J. Chem. Phys. 1979, 64, 4546-4553; S. Macura, R. R. Ernst, Mol. Phys. 1980, 41, 95-117) were carried out on a Varian UNITY instrument (750 MHz) equipped with pulse field gradient accessories. Samples consisted of 3.1 mM MK2 and 0.26 mM protease in the standard buffer at pH 7. Phase-sensitive spectra were acquired at 10°C using the time proportional phase incrementation (TPPI) method (D. Marion, K. Wüthrich, Biochem. Biophys. Res. Commun. 1983, 113, 967-974; A. G. Redfield, S. D. Kuntz, J. Magn. Res. 1975, 19, 250-254). Water suppression was achieved by inserting a 3-9-19 WATERGATE module prior to acquisition ( M. Piotto, V. Saudek, V. Sklenar, J. Biolmol. NMR 1992, 2, 661-665; V. Sklenar, M. Piotto, R. Lippek, V. Saudek, J. Magn. Reson. A 1993, 102, 241-245). The NOESY spectra were acquired using mixing times of 50, 100, 150, and 250 ms, and a selective flip-back pulse was employed just prior to the readout pulse to maintain the water magnetization along the positive z axis during acquisition and relaxation delay (G. Lippens, C. Dhalluin, C. Wieruszeski, J. Biomol. NMR 1995, 5, 327-331).
21. 2O resonance. The 2D NOESY experiments (J. Jeener, B. H. Meier, P. Bachmann, R. R. Ernst, J. Chem. Phys. 1979, 64, 4546-4553; S. Macura, R. R. Ernst, Mol. Phys. 1980, 41, 95-117) were carried out on a Varian UNITY instrument (750 MHz) equipped with pulse field gradient accessories. Samples consisted of 3.1 mM MK2 and 0.26 mM protease in the standard buffer at pH 7. Phase-sensitive spectra were acquired at 10°C using the time proportional phase incrementation (TPPI) method (D. Marion, K. Wüthrich, Biochem. Biophys. Res. Commun. 1983, 113, 967-974; A. G. Redfield, S. D. Kuntz, J. Magn. Res. 1975, 19, 250-254). Water suppression was achieved by inserting a 3-9-19 WATERGATE module prior to acquisition ( M. Piotto, V. Saudek, V. Sklenar, J. Biolmol. NMR 1992, 2, 661-665; V. Sklenar, M. Piotto, R. Lippek, V. Saudek, J. Magn. Reson. A 1993, 102, 241-245). The NOESY spectra were acquired using mixing times of 50, 100, 150, and 250 ms, and a selective flip-back pulse was employed just prior to the readout pulse to maintain the water magnetization along the positive z axis during acquisition and relaxation delay (G. Lippens, C. Dhalluin, C. Wieruszeski, J. Biomol. NMR 1995, 5, 327-331).
22. 2O resonance. The 2D NOESY experiments (J. Jeener, B. H. Meier, P. Bachmann, R. R. Ernst, J. Chem. Phys. 1979, 64, 4546-4553; S. Macura, R. R. Ernst, Mol. Phys. 1980, 41, 95-117) were carried out on a Varian UNITY instrument (750 MHz) equipped with pulse field gradient accessories. Samples consisted of 3.1 mM MK2 and 0.26 mM protease in the standard buffer at pH 7. Phase-sensitive spectra were acquired at 10°C using the time proportional phase incrementation (TPPI) method (D. Marion, K. Wüthrich, Biochem. Biophys. Res. Commun. 1983, 113, 967-974; A. G. Redfield, S. D. Kuntz, J. Magn. Res. 1975, 19, 250-254). Water suppression was achieved by inserting a 3-9-19 WATERGATE module prior to acquisition ( M. Piotto, V. Saudek, V. Sklenar, J. Biolmol. NMR 1992, 2, 661-665; V. Sklenar, M. Piotto, R. Lippek, V. Saudek, J. Magn. Reson. A 1993, 102, 241-245). The NOESY spectra were acquired using mixing times of 50, 100, 150, and 250 ms, and a selective flip-back pulse was employed just prior to the readout pulse to maintain the water magnetization along the positive z axis during acquisition and relaxation delay (G. Lippens, C. Dhalluin, C. Wieruszeski, J. Biomol. NMR 1995, 5, 327-331).
23. 2O resonance. The 2D NOESY experiments (J. Jeener, B. H. Meier, P. Bachmann, R. R. Ernst, J. Chem. Phys. 1979, 64, 4546-4553; S. Macura, R. R. Ernst, Mol. Phys. 1980, 41, 95-117) were carried out on a Varian UNITY instrument (750 MHz) equipped with pulse field gradient accessories. Samples consisted of 3.1 mM MK2 and 0.26 mM protease in the standard buffer at pH 7. Phase-sensitive spectra were acquired at 10°C using the time proportional phase incrementation (TPPI) method (D. Marion, K. Wüthrich, Biochem. Biophys. Res. Commun. 1983, 113, 967-974; A. G. Redfield, S. D. Kuntz, J. Magn. Res. 1975, 19, 250-254). Water suppression was achieved by inserting a 3-9-19 WATERGATE module prior to acquisition ( M. Piotto, V. Saudek, V. Sklenar, J. Biolmol. NMR 1992, 2, 661-665; V. Sklenar, M. Piotto, R. Lippek, V. Saudek, J. Magn. Reson. A 1993, 102, 241-245). The NOESY spectra were acquired using mixing times of 50, 100, 150, and 250 ms, and a selective flip-back pulse was employed just prior to the readout pulse to maintain the water magnetization along the positive z axis during acquisition and relaxation delay (G. Lippens, C. Dhalluin, C. Wieruszeski, J. Biomol. NMR 1995, 5, 327-331).
24. 2O resonance. The 2D NOESY experiments (J. Jeener, B. H. Meier, P. Bachmann, R. R. Ernst, J. Chem. Phys. 1979, 64, 4546-4553; S. Macura, R. R. Ernst, Mol. Phys. 1980, 41, 95-117) were carried out on a Varian UNITY instrument (750 MHz) equipped with pulse field gradient accessories. Samples consisted of 3.1 mM MK2 and 0.26 mM protease in the standard buffer at pH 7. Phase-sensitive spectra were acquired at 10°C using the time proportional phase incrementation (TPPI) method (D. Marion, K. Wüthrich, Biochem. Biophys. Res. Commun. 1983, 113, 967-974; A. G. Redfield, S. D. Kuntz, J. Magn. Res. 1975, 19, 250-254). Water suppression was achieved by inserting a 3-9-19 WATERGATE module prior to acquisition ( M. Piotto, V. Saudek, V. Sklenar, J. Biolmol. NMR 1992, 2, 661-665; V. Sklenar, M. Piotto, R. Lippek, V. Saudek, J. Magn. Reson. A 1993, 102, 241-245). The NOESY spectra were acquired using mixing times of 50, 100, 150, and 250 ms, and a selective flip-back pulse was employed just prior to the readout pulse to maintain the water magnetization along the positive z axis during acquisition and relaxation delay (G. Lippens, C. Dhalluin, C. Wieruszeski, J. Biomol. NMR 1995, 5, 327-331).
25. 2O resonance. The 2D NOESY experiments (J. Jeener, B. H. Meier, P. Bachmann, R. R. Ernst, J. Chem. Phys. 1979, 64, 4546-4553; S. Macura, R. R. Ernst, Mol. Phys. 1980, 41, 95-117) were carried out on a Varian UNITY instrument (750 MHz) equipped with pulse field gradient accessories. Samples consisted of 3.1 mM MK2 and 0.26 mM protease in the standard buffer at pH 7. Phase-sensitive spectra were acquired at 10°C using the time proportional phase incrementation (TPPI) method (D. Marion, K. Wüthrich, Biochem. Biophys. Res. Commun. 1983, 113, 967-974; A. G. Redfield, S. D. Kuntz, J. Magn. Res. 1975, 19, 250-254). Water suppression was achieved by inserting a 3-9-19 WATERGATE module prior to acquisition ( M. Piotto, V. Saudek, V. Sklenar, J. Biolmol. NMR 1992, 2, 661-665; V. Sklenar, M. Piotto, R. Lippek, V. Saudek, J. Magn. Reson. A 1993, 102, 241-245). The NOESY spectra were acquired using mixing times of 50, 100, 150, and 250 ms, and a selective flip-back pulse was employed just prior to the readout pulse to maintain the water magnetization along the positive z axis during acquisition and relaxation delay (G. Lippens, C. Dhalluin, C. Wieruszeski, J. Biomol. NMR 1995, 5, 327-331).
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28. -1; root mean square deviation for all heavy atoms: 0.241), and a representative consistent with the NMR data was selected.
29. L. Tong, C. Qian, M.-J. Massariol, R. Déziel, C. Yoakim, L. Lagacé, Nature Struct. Biol., in press.