HIV-1 protease with 20 mutations exhibits extreme resistance to clinical inhibitors through coordinated structural rearrangements

Biochemistry

Volumn 51, Issue 13, 2012, Pages 2819-2828

  Agniswamy, Johnson ^a   Shen, Chen Hsiang ^a   Aniana, Annie ^b   Sayer, Jane M ^b   Louis, John M ^b   Weber, Irene T ^a  

^a GEORGIA STATE UNIVERSITY   (United States)

^b NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVE SITE; AROMATIC SIDE CHAINS; CLOSED FORM; HIV-1 PROTEASE; HYDROPHOBIC CONTACT; INTERSUBUNIT INTERACTION; MULTIPLE MUTATIONS; OPEN CONFORMATION; ORDERS OF MAGNITUDE; PI INTERACTIONS; PROTEASE INHIBITOR; SAQUINAVIR; STRUCTURAL REARRANGEMENT; WILD TYPES;

CONFORMATIONS; ENZYME INHIBITION; HYDROGEN BONDS; YTTRIUM;

COORDINATION REACTIONS;

DARUNAVIR; DIMER; HUMAN IMMUNODEFICIENCY VIRUS PROTEINASE; PROTEIN PR20; SAQUINAVIR; UNCLASSIFIED DRUG; YTTRIUM;

ARTICLE; BINDING AFFINITY; CRYSTAL STRUCTURE; DRUG BINDING SITE; DRUG PROTEIN BINDING; DRUG RESISTANCE; ENZYME SUBSTRATE; HUMAN; HYDROGEN BOND; HYDROPHOBICITY; MUTATION; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN PROCESSING; PROTEIN STRUCTURE; WILD TYPE;

AMINO ACID SEQUENCE; CRYSTALLOGRAPHY, X-RAY; DRUG RESISTANCE, VIRAL; HIV PROTEASE; HIV PROTEASE INHIBITORS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MUTATION;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 84859383561     PISSN: 00062960     EISSN: 15204995     Source Type: Journal    
DOI: 10.1021/bi2018317     Document Type: Article

References (51)

1. Kohl, N. E., Emini, E. A., Schleif, W. A., Davis, L. J., Heimbach, J. C., Dixon, R. A., Scolnick, E. M., and Sigal, I. S. (1988) Active human immunodeficiency virus protease is required for viral infectivity Proc. Natl. Acad. Sci. U. S. A. 85, 4686-4690
2. Ridky, T. and Leis, J. (1995) Development of drug resistance to HIV-1 protease inhibitors J. Biol. Chem. 270, 29621-29623
3. Ho, D. D., Neumann, A. U., Perelson, A. S., Chen, W., Leonard, J. M., and Markowitz, M. (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection Nature 373, 123-126
4. Croteau, G., Doyon, L., Thibeault, D., McKercher, G., Pilote, L., and Lamarre, D. (1997) Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors J. Virol. 71, 1089-1096
5. Mammano, F., Trouplin, V., Zennou, V., and Clavel, F. (2000) Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug J. Virol. 74, 8524-8531
6. Johnson, V. A., Brun-Vezinet, F., Clotet, B., Gunthard, H. F., Kuritzkes, D. R., Pillay, D., Schapiro, J. M., and Richman, D. D. (2010) Update of the Drug Resistance Mutations in HIV-1: December 2010. Top. HIV Med. 18, 156-163.
7. Winters, M. A. and Merigan, T. C. (2005) Insertions in the human immunodeficiency virus type 1 protease and reverse transcriptase genes: clinical impact and molecular mechanisms Antimicrob. Agents Chemother. 49, 2575-2582
8. Kozisek, M., Saskova, K. G., Rezacova, P., Brynda, J., van Maarseveen, N. M., De Jong, D., Boucher, C. A., Kagan, R. M., Nijhuis, M., and Konvalinka, J. (2008) Ninety-nine is not enough: molecular characterization of inhibitor-resistant human immunodeficiency virus type 1 protease mutants with insertions in the flap region J. Virol. 82, 5869-5878
9. Maguire, M. F., Guinea, R., Griffin, P., Macmanus, S., Elston, R. C., Wolfram, J., Richards, N., Hanlon, M. H., Porter, D. J., Wrin, T., Parkin, N., Tisdale, M., Furfine, E., Petropoulos, C., Snowden, B. W., and Kleim, J. P. (2002) Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro J. Virol. 76, 7398-7406
10. Agniswamy, J. and Weber, I. T. (2009) HIV-1 protease: structural prespectives on drug resistance Viruses 1, 1110-1136
11. Louis, J. M., Aniana, A., Weber, I. T., and Sayer, J. M. (2011) Inhibition of autoprocessing of natural variants and multidrug resistant mutant precursors of HIV-1 protease by clinical inhibitors Proc. Natl. Acad. Sci. U. S. A. 108, 9072-9077
12. Dierynck, I., De Wit, M., Gustin, E., Keuleers, I., Vandersmissen, J., Hallenberger, S., and Hertogs, K. (2007) Binding kinetics of darunavir to human immunodeficiency virus type 1 protease explain the potent antiviral activity and high genetic barrier J. Virol. 81, 13845-13851
13. Sayer, J. M. and Louis, J. M. (2009) Interactions of different inhibitors with active-site aspartyl residues of HIV-1 protease and possible relevance to pepsin Proteins 75, 556-568
14. Sayer, J. M., Agniswamy, J., Weber, I. T., and Louis, J. M. (2010) Autocatalytic maturation, physical/chemical properties, and crystal structure of group N HIV-1 protease: relevance to drug resistance Protein Sci. 19, 2055-2072
15. Otwinowski, Z. and Minor, W. (1997) Processing of X-ray diffraction data collected in oscillation mode Methods Enzymol. 276, 307-326
16. Tie, Y., Boross, P. I., Wang, Y. F., Gaddis, L., Hussain, A. K., Leshchenko, S., Ghosh, A. K., Louis, J. M., Harrison, R. W., and Weber, I. T. (2004) High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains J. Mol. Biol. 338, 341-352
17. McCoy, A. J., Grosse-Kunstleve, R. W., Storoni, L. C., and Read, R. J. (2005) Likelihood-enhanced fast translation functions Acta Crystallogr., Sect. D: Biol. Crystallogr. 61, 458-464
18. Storoni, L. C., McCoy, A. J., and Read, R. J. (2004) Likelihood-enhanced fast rotation functions Acta Crystallogr., Sect. D: Biol. Crystallogr. 60, 432-438
19. Kovalevsky, A. Y., Tie, Y., Liu, F., Boross, P. I., Wang, Y. F., Leshchenko, S., Ghosh, A. K., Harrison, R. W., and Weber, I. T. (2006) Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M J. Med. Chem. 49, 1379-1387
20. Sheldrick, G. M. and Schneider, T. R. (1997) SHELXL: high-resolution refinement Methods Enzymol. 277, 319-343
21. Emsley, P. and Cowtan, K. (2004) Coot: model-building tools for molecular graphics Acta Crystallogr., Sect. D: Biol. Crystallogr. 60, 2126-2132
22. Murshudov, G. N., Vagin, A. A., and Dodson, E. J. (1997) Refinement of macromolecular structures by the maximum-likelihood method Acta Crystallogr., Sect. D: Biol. Crystallogr. 53, 240-255
23. Heaslet, H., Rosenfeld, R., Giffin, M., Lin, Y. C., Tam, K., Torbett, B. E., Elder, J. H., McRee, D. E., and Stout, C. D. (2007) Conformational flexibility in the flap domains of ligand-free HIV protease Acta Crystallogr., Sect. D: Biol. Crystallogr. 63, 866-875
24. Martin, P., Vickrey, J. F., Proteasa, G., Jimenez, Y. L., Wawrzak, Z., Winters, M. A., Merigan, T. C., and Kovari, L. C. (2005) "Wide-open" 1.3 A structure of a multidrug-resistant HIV-1 protease as a drug target Structure 13, 1887-1895
25. Sayer, J. M., Liu, F., Ishima, R., Weber, I. T., and Louis, J. M. (2008) Effect of the active site D25N mutation on the structure, stability, and ligand binding of the mature HIV-1 protease J. Biol. Chem. 283, 13459-13470
26. Woon, T. C., Brinkworth, R. I., and Fairlie, D. P. (1992) Inhibition of HIV-1 proteinase by metal ions Int. J. Biochem. 24, 911-914
27. Wlodawer, A., Miller, M., Jaskolski, M., Sathyanarayana, B. K., Baldwin, E., Weber, I. T., Selk, L. M., Clawson, L., Schneider, J., and Kent, S. B. (1989) Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease Science 245, 616-621
28. Kear, J. L., Blackburn, M. E., Veloro, A. M., Dunn, B. M., and Fanucci, G. E. (2009) Subtype polymorphisms among HIV-1 protease variants confer altered flap conformations and flexibility J. Am. Chem. Soc. 131, 14650-14651
29. Tie, Y., Boross, P. I., Wang, Y. F., Gaddis, L., Liu, F., Chen, X., Tozser, J., Harrison, R. W., and Weber, I. T. (2005) Molecular basis for substrate recognition and drug resistance from 1.1 to 1.6 angstroms resolution crystal structures of HIV-1 protease mutants with substrate analogs FEBS J. 272, 5265-5277
30. Liu, Z., Wang, Y., Brunzelle, J., Kovari, I. A., and Kovari, L. C. (2011) Nine crystal structures determine the substrate envelope of the MDR HIV-1 protease Protein J. 30, 173-183
31. Swairjo, M. A., Towler, E. M., Debouck, C., and Abdel-Meguid, S. S. (1998) Structural role of the 30s loop in determining the ligand specificity of the human immunodeficiency virus protease Biochemistry 37, 10928-10936
32. Meiselbach, H., Horn, A. H., Harrer, T., and Sticht, H. (2007) Insights into amprenavir resistance in E35D HIV-1 protease mutation from molecular dynamics and binding free-energy calculations J. Mol. Model. 13, 297-304
33. Ode, H., Matsuyama, S., Hata, M., Neya, S., Kakizawa, J., Sugiura, W., and Hoshino, T. (2007) Computational characterization of structural role of the non-active site mutation M36I of human immunodeficiency virus type 1 protease J. Mol. Biol. 370, 598-607
34. Sanches, M., Krauchenco, S., Martins, N. H., Gustchina, A., Wlodawer, A., and Polikarpov, I. (2007) Structural characterization of B and non-B subtypes of HIV-protease: insights into the natural susceptibility to drug resistance development J. Mol. Biol. 369, 1029-1040
35. Clemente, J. C., Moose, R. E., Hemrajani, R., Whitford, L. R., Govindasamy, L., Reutzel, R., McKenna, R., Agbandje-McKenna, M., Goodenow, M. M., and Dunn, B. M. (2004) Comparing the accumulation of active- and nonactive-site mutations in the HIV-1 protease Biochemistry 43, 12141-12151
36. Tie, Y., Kovalevsky, A. Y., Boross, P., Wang, Y. F., Ghosh, A. K., Tozser, J., Harrison, R. W., and Weber, I. T. (2007) Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir Proteins 67, 232-242
37. Kovalevsky, A. Y., Liu, F., Leshchenko, S., Ghosh, A. K., Louis, J. M., Harrison, R. W., and Weber, I. T. (2006) Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114 J. Mol. Biol. 363, 161-173
38. Tie, Y., Wang, Y. F., Boross, P. I., Chiu, T. Y., Ghosh, A. K., Tozser, J., Louis, J. M., Harrison, R. W., and Weber, I. T. (2011) Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors Protein Sci. 21, 339-350
39. Louis, J. M., Zhang, Y., Sayer, J. M., Wang, Y. F., Harrison, R. W., and Weber, I. T. (2011) The L76V Drug Resistance Mutation Decreases the Dimer Stability and Rate of Autoprocessing of HIV-1 Protease by Reducing Internal Hydrophobic Contacts Biochemistry 50, 4786-4795
40. Saskova, K. G., Kozisek, M., Rezacova, P., Brynda, J., Yashina, T., Kagan, R. M., and Konvalinka, J. (2009) Molecular characterization of clinical isolates of human immunodeficiency virus resistant to the protease inhibitor darunavir J Virol. 83, 8810-8818
41. Bandaranayake, R. M., Kolli, M., King, N. M., Nalivaika, E. A., Heroux, A., Kakizawa, J., Sugiura, W., and Schiffer, C. A. (2010) The effect of clade-specific sequence polymorphisms on HIV-1 protease activity and inhibitor resistance pathways J. Virol. 84, 9995-10003
42. Mitsuya, Y., Winters, M. A., Fessel, W. J., Rhee, S. Y., Hurley, L., Horberg, M., Schiffer, C. A., Zolopa, A. R., and Shafer, R. W. (2006) N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure AIDS Res. Hum. Retroviruses 22, 1300-1305
43. Mahalingam, B., Wang, Y. F., Boross, P. I., Tozser, J., Louis, J. M., Harrison, R. W., and Weber, I. T. (2004) Crystal structures of HIV protease V82A and L90M mutants reveal changes in the indinavir-binding site Eur. J. Biochem. 271, 1516-1524
44. Shen, C. H., Wang, Y. F., Kovalevsky, A. Y., Harrison, R. W., and Weber, I. T. (2010) Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters FEBS J. 277, 3699-3714
45. Kozisek, M., Bray, J., Rezacova, P., Saskova, K., Brynda, J., Pokorna, J., Mammano, F., Rulisek, L., and Konvalinka, J. (2007) Molecular analysis of the HIV-1 resistance development: enzymatic activities, crystal structures, and thermodynamics of nelfinavir-resistant HIV protease mutants J. Mol. Biol. 374, 1005-1016
46. Mahalingam, B., Louis, J. M., Reed, C. C., Adomat, J. M., Krouse, J., Wang, Y. F., Harrison, R. W., and Weber, I. T. (1999) Structural and kinetic analysis of drug resistant mutants of HIV-1 protease Eur. J. Biochem. 263, 238-245
47. Manchester, M., Everitt, L., Loeb, D. D., Hutchison, C. A., III, and Swanstrom, R. (1994) Identification of temperature-sensitive mutants of the human immunodeficiency virus type 1 protease through saturation mutagenesis. Amino acid side chain requirements for temperature sensitivity J. Biol. Chem. 269, 7689-7695
48. Wang, Y., Liu, Z., Brunzelle, J. S., Kovari, I. A., Dewdney, T. G., Reiter, S. J., and Kovari, L. C. (2011) The higher barrier of darunavir and tipranavir resistance for HIV-1 protease Biochem. Biophys. Res. Commun. 412, 737-742
49. Ghosh, A. K., Xu, C. X., Rao, K. V., Baldridge, A., Agniswamy, J., Wang, Y. F., Weber, I. T., Aoki, M., Miguel, S. G., Amano, M., and Mitsuya, H. (2010) Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors ChemMedChem 5, 1850-1854
50. Kozisek, M., Cigler, P., Lepsik, M., Fanfrlik, J., Rezacova, P., Brynda, J., Pokorna, J., Plesek, J., Gruner, B., Grantz Saskova, K., Vaclavikova, J., Kral, V., and Konvalinka, J. (2008) Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance J. Med. Chem. 51, 4839-4843
51. Bottcher, J., Blum, A., Dorr, S., Heine, A., Diederich, W. E., and Klebe, G. (2008) Targeting the open-flap conformation of HIV-1 protease with pyrrolidine-based inhibitors ChemMedChem 3, 1337-1344