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Nine Crystal Structures Determine the Substrate Envelope of the MDR HIV-1 Protease

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Abstract

Under drug selection pressure, emerging mutations render HIV-1 protease drug resistant, leading to the therapy failure in anti-HIV treatment. It is known that nine substrate cleavage site peptides bind to wild type (WT) HIV-1 protease in a conserved pattern. However, how the multidrug-resistant (MDR) HIV-1 protease binds to the substrate cleavage site peptides is yet to be determined. MDR769 HIV-1 protease (resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90) was selected for present study to understand the binding to its natural substrates. MDR769 HIV-1 protease was co-crystallized with nine substrate cleavage site hepta-peptides. Crystallographic studies show that MDR769 HIV-1 protease has an expanded substrate envelope with wide open flaps. Furthermore, ligand binding energy calculations indicate weaker binding in MDR769 HIV-1 protease-substrate complexes. These results help in designing the next generation of HIV-1 protease inhibitors by targeting the MDR HIV-1 protease.

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Abbreviations

MDR:

Multi-drug resistance

HIV:

Human immunodeficiency virus

WT:

Wild type

HAART:

Highly active antiretroviral therapy

PR:

Protease

MA:

Matrix

CA:

Capsid

NC:

Nucleocapsid

RT:

Reverse transcriptase

IN:

Integrase

RH:

RNase H

RMSD:

Root mean square deviation

References

  1. Altman MD, Ali A, Reddy GS, Nalam MN, Anjum SG, Cao H, Chellappan S, Kairys V, Fernandes MX, Gilson MK, Schiffer CA, Rana TM, Tidor B (2008) J Am Chem Soc 130:6099–6113

    Article  CAS  Google Scholar 

  2. Bally F, Martinez R, Peters S, Sudre P, Telenti A (2000) AIDS Res Hum Retroviruses 16:1209–1213

    Article  CAS  Google Scholar 

  3. Barbaro G, Lucchini A, Barbarini G (2005) Minerva Cardioangiol 53:153–154

    CAS  Google Scholar 

  4. Bartlett JA, DeMasi R, Quinn J, Moxham C, Rousseau F (2001) AIDS 15:1369–1377

    Article  CAS  Google Scholar 

  5. Chellappan S, Kairys V, Fernandes MX, Schiffer C, Gilson MK (2007) Proteins 68:561–567

    Article  CAS  Google Scholar 

  6. Chellappan S, Kiran Kumar Reddy GS, Ali A, Nalam MN, Anjum SG, Cao H, Kairys V, Fernandes MX, Altman MD, Tidor B, Rana TM, Schiffer CA, Gilson MK (2007) Chem Biol Drug Des 69:298–313

    Article  CAS  Google Scholar 

  7. Clavel F, Hance AJ (2004) N Engl J Med 350:1023–1035

    CAS  Google Scholar 

  8. Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M (1995) Nature 374:569–571

    Article  CAS  Google Scholar 

  9. Croteau G, Doyon L, Thibeault D, McKercher G, Pilote L, Lamarre D (1997) J Virol 71:1089–1096

    CAS  Google Scholar 

  10. Emsley P, Cowtan K (2004) Acta Crystallogr D Biol Crystallogr 60:2126–2132

    Article  Google Scholar 

  11. Grabar S, Pradier C, Le Corfec E, Lancar R, Allavena C, Bentata M, Berlureau P, Dupont C, Fabbro-Peray P, Poizot-Martin I, Costagliola D (2000) AIDS 14:141–149

    Article  CAS  Google Scholar 

  12. Gulick RM, Mellors JW, Havlir D, Eron JJ, Meibohm A, Condra JH, Valentine FT, McMahon D, Gonzalez C, Jonas L, Emini EA, Chodakewitz JA, Isaacs R, Richman DD (2000) Ann Intern Med 133:35–39

    CAS  Google Scholar 

  13. Holzgrabe U (2004) Pharm Unserer Zeit 33:160

    Google Scholar 

  14. Krissinel E, Henrick K (2004) Acta Crystallogr D Biol Crystallogr 60:2256–2268

    Article  CAS  Google Scholar 

  15. Krissinel E, Henrick K (2007) J Mol Biol 372:774–797

    Article  CAS  Google Scholar 

  16. Laemmli UK (1970) Nature 227:680–685

    Article  CAS  Google Scholar 

  17. Lamzin VS, Wilson KS (1993) Acta Crystallogr D Biol Crystallogr 49:129–147

    Article  CAS  Google Scholar 

  18. Li F, Goila-Gaur R, Salzwedel K, Kilgore NR, Reddick M, Matallana C, Castillo A, Zoumplis D, Martin DE, Orenstein JM, Allaway GP, Freed EO, Wild CT (2003) Proc Natl Acad Sci USA 100:13555–13560

    Article  CAS  Google Scholar 

  19. Li F, Zoumplis D, Matallana C, Kilgore NR, Reddick M, Yunus AS, Adamson CS, Salzwedel K, Martin DE, Allaway GP, Freed EO, Wild CT (2006) Virology 356:217–224

    Article  CAS  Google Scholar 

  20. Logsdon BC, Vickrey JF, Martin P, Proteasa G, Koepke JI, Terlecky SR, Wawrzak Z, Winters MA, Merigan TC, Kovari LC (2004) J Virol 78:3123–3132

    Article  CAS  Google Scholar 

  21. Martin DE, Blum R, Wilton J, Doto J, Galbraith H, Burgess GL, Smith PC, Ballow C (2007) Antimicrob Agents Chemother 51:3063–3066

    Article  CAS  Google Scholar 

  22. Martin P, Vickrey JF, Proteasa G, Jimenez YL, Wawrzak Z, Winters MA, Merigan TC, Kovari LC (2005) Structure 13:1887–1895

    Article  CAS  Google Scholar 

  23. McMichael AJ, Hanke T (2003) Nat Med 9:874–880

    Article  CAS  Google Scholar 

  24. Murshudov GN, Vagin AA, Dodson EJ (1997) Acta Crystallogr D Biol Crystallogr 53:240–255

    Article  CAS  Google Scholar 

  25. Nalam MN, Ali A, Altman MD, Reddy GS, Chellappan S, Kairys V, Ozen A, Cao H, Gilson MK, Tidor B, Rana TM, Schiffer CA (2010) J Virol 84:5368–5378

    Article  CAS  Google Scholar 

  26. Natarajan V, Bosche M, Metcalf JA, Ward DJ, Lane HC, Kovacs JA (1999) Lancet 353:119–120

    Article  CAS  Google Scholar 

  27. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD (1998) N Engl J Med 338:853–860

    Article  Google Scholar 

  28. Pettit SC, Everitt LE, Choudhury S, Dunn BM, Kaplan AH (2004) J Virol 78:8477–8485

    Article  CAS  Google Scholar 

  29. Prabu-Jeyabalan M, King NM, Nalivaika EA, Heilek-Snyder G, Cammack N, Schiffer CA (2006) Antimicrob Agents Chemother 50:1518–1521

    Article  CAS  Google Scholar 

  30. Prabu-Jeyabalan M, Nalivaika EA, King NM, Schiffer CA (2004) J Virol 78:12446–12454

    Article  CAS  Google Scholar 

  31. Prabu-Jeyabalan M, Nalivaika EA, Romano K, Schiffer CA (2006) J Virol 80:3607–3616

    Article  CAS  Google Scholar 

  32. Prabu-Jeyabalan M, Nalivaika E, Schiffer CA (2000) J Mol Biol 301:1207–1220

    Article  CAS  Google Scholar 

  33. Prabu-Jeyabalan M, Nalivaika E, Schiffer CA (2002) Structure 10:369–381

    Article  CAS  Google Scholar 

  34. Roberts JD, Preston BD, Johnston LA, Soni A, Loeb LA, Kunkel TA (1989) Mol Cell Biol 9:469–476

    CAS  Google Scholar 

  35. Robinson LH, Myers RE, Snowden BW, Tisdale M, Blair ED (2000) AIDS Res Hum Retroviruses 16:1149–1156

    Article  CAS  Google Scholar 

  36. Schooley RT, Mellors JW (2007) J Infect Dis 195:770–772

    Article  CAS  Google Scholar 

  37. Sukasem C, Churdboonchart V, Sukeepaisarncharoen W, Piroj W, Inwisai T, Tiensuwan M, Chantratita W (2008) Int J Antimicrob Agents 31:277–281

    CAS  Google Scholar 

  38. Takeuchi Y, Nagumo T, Hoshino H (1988) J Virol 62:3900–3902

    CAS  Google Scholar 

  39. Tie Y, Boross PI, Wang YF, Gaddis L, Liu F, Chen X, Tozser J, Harrison RW, Weber IT (2005) FEBS J 272:5265–5277

    Article  CAS  Google Scholar 

  40. Vagin AA, Steiner RA, Lebedev AA, Potterton L, McNicholas S, Long F, Murshudov GN (2004) Acta Crystallogr D Biol Crystallogr 60:2184–2195

    Article  Google Scholar 

  41. Vaguine AA, Richelle J, Wodak SJ (1999) Acta Crystallogr D Biol Crystallogr 55:191–205

    Article  CAS  Google Scholar 

  42. Vickrey JF, Logsdon BC, Proteasa G, Palmer S, Winters MA, Merigan TC, Kovari LC (2003) Protein Expr Purif 28:165–172

    Article  CAS  Google Scholar 

  43. Wallace AC, Laskowski RA, Thornton JM (1995) Protein Eng 8:127–134

    Article  CAS  Google Scholar 

  44. Weber J, Grosse F (1989) Nucleic Acids Res 17:1379–1393

    Article  CAS  Google Scholar 

  45. Zhang YM, Imamichi H, Imamichi T, Lane HC, Falloon J, Vasudevachari MB, Salzman NP (1997) J Virol 71:6662–6670

    CAS  Google Scholar 

  46. Zhou J, Chen CH, Aiken C (2004) Retrovirology 1:15

    Article  Google Scholar 

Download references

Acknowledgments

This research was supported by the National Institutes of Health grant AI65294 and a grant from the American Foundation for AIDS Research (106457-34-RGGN).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Wayne State University, School of Medicine, 540 E. Canfield Avenue, 4263 Scott Hall, Detroit, MI, 48201, USA

    Zhigang Liu, Yong Wang, Iulia A. Kovari & Ladislau C. Kovari

  2. Life Sciences Collaborative Access Team, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine Chicago, Chicago, IL, 60611, USA

    Joseph Brunzelle

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  1. Zhigang Liu
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  2. Yong Wang
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  4. Iulia A. Kovari
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  5. Ladislau C. Kovari
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Correspondence to Ladislau C. Kovari.

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Liu, Z., Wang, Y., Brunzelle, J. et al. Nine Crystal Structures Determine the Substrate Envelope of the MDR HIV-1 Protease. Protein J 30, 173–183 (2011). https://doi.org/10.1007/s10930-011-9316-2

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