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Molecular and structural determinants of adamantyl susceptibility to HLA-DRs allelic variants: an in silico approach to understand the mechanism of MLEs

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Abstract

Class II major histocompatibility complex (MHC II) molecules as expressed by antigen-presenting cells are heterodimeric cell-surface glycoprotein receptors that are fundamental in initiating and propagating an immune response by presenting tumor-associated antigenic peptides to CD4+/TH cells. The loading efficiency of such peptides can be improved by small organic compounds (MHC Loading Enhancers—MLEs), that convert the non-receptive peptide conformation of MHC II to a peptide-receptive conformation. In a reversible reaction, these compounds open up the binding site of MHC II molecules by specific interactions with a yet undefined pocket. Here, we performed molecular docking and molecular dynamics simulation studies of adamantyl compounds on the predicted cavity around the P1 pocket of 2 allelic variants of HLA-DRs. The purpose was to investigate the suitability of adamantyl compounds as MLEs at the dimorphic β86 position. Docking studies revealed that besides numerous molecular interactions formed by the adamantyl compounds, Asnβ82, Tyrβ83, and Thrβ90 are the crucial amino acid residues that are characterized as the “sensors” of peptide loading. Molecular dynamics simulation studies exposed the dynamical structural changes that HLA-DRs adopted as a response to binding of 3-(1-adamantyl)-5-hydrazidocarbonyl-1H-pyrazole (AdCaPy). The conformations of AdCaPy complexed with the Glyβ86 HLA-DR allelic variant are well correlated with the stabilized form of peptide-loaded HLA-DRs, further confirming the role of AdCaPy as a MLE. Hydrogen bonding interaction analysis clearly demonstrated that after making suitable contacts with AdCaPy, HLA-DR changes its local conformation. However, AdCaPy complexed with HLA-DR having Valβ86 at the dimorphic position did not accommodate AdCaPy as MLE due to steric hindrance caused by the valine.

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References

  1. Corthay A, Skovseth DK, Lundin KU, Røsjø E, Omholt H, Hofgaard PO, Haraldsen G, Bogen B (2005) Immunity 22:371–383

    Article  CAS  Google Scholar 

  2. Stern LJ, Potolicchio I, Santambrogio L (2006) Curr Opin Immunol 18:64–69

    Article  CAS  Google Scholar 

  3. Watts C (2001) Curr Opin Immunol 13:26–31

    Article  CAS  Google Scholar 

  4. McFarland BJ, Beeson C (2002) Med Res Rev 22:168–203

    Article  CAS  Google Scholar 

  5. Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC (1994) Nature 368:215–221

    Article  CAS  Google Scholar 

  6. Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC (1993) Nature 364:33–39

    Article  CAS  Google Scholar 

  7. Hansen TH, Lybarger L, Yu L, Mitaksov V, Fremont DH (2005) Immunol Rev 207:100–111

    Article  CAS  Google Scholar 

  8. Carven GJ, Chitta S, Hilgert I, Rushe MM, Baggio RF, Palmer M, Arenas JE, Strominger JL, Horejsi V, Santambrogio L (2004) J Biol Chem 279:16561–16570

    Article  CAS  Google Scholar 

  9. Painter CA, Cruz A, López GE, Stern LJ, Zavala-Ruiz Z (2008) PLoS ONE 3:e2403

    Article  Google Scholar 

  10. Zarutskie JA, Sato AK, Rushe MM, Chan IC, Lomakin A, Benedek GB, Stern LJ (1999) Biochemistry 38:5878–5887

    Article  CAS  Google Scholar 

  11. Chou CL, Sadegh-Nasseri S (2000) J Exp Med 192:1697–1706

    Article  CAS  Google Scholar 

  12. Rabinowitz JD, Vrljic M, Kasson PM, Liang MN, Busch R, Boniface JJ, Davis MM, McConnell HM (1998) Immunity 9:699–710

    Article  CAS  Google Scholar 

  13. Schmitt L, Boniface JJ, Davis MM, McConnell HM (1999) J Mol Biol 286:207–218

    Article  CAS  Google Scholar 

  14. Kalams SA, Walker BD (1998) J Exp Med 188:2199–2204

    Article  CAS  Google Scholar 

  15. Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H (1998) J Exp Med 188:2357–2368

    Article  CAS  Google Scholar 

  16. Marin-Esteban V, Falk K, Rötzschke O (2003) J Autoimmune 20:63–69

    Article  CAS  Google Scholar 

  17. Marin-Esteban V, Falk K, Rotzschke O (2004) J Biol Chem 279:50684–50690

    Article  CAS  Google Scholar 

  18. Nicholson MJ, Moradi B, Seth NP, Xing X, Cuny GD, Stein RL, Wucherpfennig KW (2006) J Immunol 176:4208–4220

    CAS  Google Scholar 

  19. Hopner S, Dickhaut K, Hofstatter M, Kramer H, Ruckerl D, Soderhall JA, Gupta S, Marin-Esteban V, Kuhne R, Freund C (2006) J Biol Chem 281:38535–38542

    Article  Google Scholar 

  20. Gupta S, Höpner S, Rupp B, Günther S, Dickhaut K, Agarwal N, Cardoso MC, Kühne R, Wiesmüller KH, Jung G (2008) PLoS ONE 3:e1814

    Article  Google Scholar 

  21. Falk K, Lau JM, Santambrogio L, Esteban VM, Puentes F, Rötzschke O, Strominger JL (2002) J Biol Chem 277:2709–2715

    Article  CAS  Google Scholar 

  22. Jones EY, Fugger L, Strominger JL, Siebold C (2006) Nat Rev Immunol 6:271–282

    Article  CAS  Google Scholar 

  23. Pinet V, Vergelli M, Martini R, Bakke O, Long EO (1995) Nat 375:603–606

    Article  CAS  Google Scholar 

  24. Vergelli M, Pinet V, Vogt AB, Kalbus M, Malnati M, Riccio P, Long EO, Martin R (1997) Eur J Immunol 27:941–951

    Article  CAS  Google Scholar 

  25. Santambrogio L, Sato AK, Carven GJ, Belyanskaya SL, Strominger JL, Stern LJ (1999) Proc Natl Acad Sci 96:15056–15061

    Article  CAS  Google Scholar 

  26. Santambrogio L, Sato AK, Fischer FR, Dorf ME, Stern LJ (1999) Proc Natl Acad Sci 96:15050–15055

    Article  CAS  Google Scholar 

  27. Dickhaut K, Hoepner S, Eckhard J, Wiesmueller KH, Schindler L, Jung G, Falk K, Roetzschke O (2009) PLoS One 4:e6811

    Article  Google Scholar 

  28. Warren GL, Andrews CW, Capelli AM, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S (2006) J Med Chem 49:5912–5931

    Article  CAS  Google Scholar 

  29. International hwtcT

  30. Gasteiger J, Marsili M (1980) Tetrahedron 36:3219–3228

    Article  CAS  Google Scholar 

  31. Clark M, Cramer RD, Opdenbosch NV (1989) J Comp Chem 10:982–1012

    Article  CAS  Google Scholar 

  32. Berman HM (2007) Acta Cryst 64:88–95

    Google Scholar 

  33. Murthy VL, Stern LJ (1997) Struct 5:1385–1396

    Article  CAS  Google Scholar 

  34. Stern LJ, Wiley DC (1994) Structure 2:245–251

    Article  CAS  Google Scholar 

  35. Smith KJ, Pyrdol J, Gauthier L, Wiley DC, Wucherpfennig KW (1998) J Exp Med 188:1511–1520

    Article  CAS  Google Scholar 

  36. Li Y, Li H, Martin R, Mariuzza RA (2000) J Mol Biol 304:177–188

    Article  CAS  Google Scholar 

  37. Thomsen R, Christensen MH (2006) J Med Chem 49:3315–3321

    Article  CAS  Google Scholar 

  38. Z M (1992) Spinger, Berlin

  39. Michalewiez ZFD (2000) How to solve it: modern heuristics. Spinger, Berlin

    Google Scholar 

  40. Gehlhaar DK, Verkhivker G, Rejto PA, Fogel DB, Fogel LJ, Freer ST (1995) In: McDonnell JR, Reynolds RG, Fogel DB (eds) Proceedings of the fourth international conference on evolutionary programming. Massachusetts Institute of Technology, USA

    Google Scholar 

  41. Gehlhaar DK, Bouzida D, Rejto PA (1998) In: Porto VW, Saravanan N, Waagen DE, Eiben AE (eds) Proceedings of the seventh international conference on evolutionary programming. Springer, USA

    Google Scholar 

  42. Yang JM, Chen CC (2004) Proteins 55:288–304

    Article  CAS  Google Scholar 

  43. Aaqvist J (1990) J Phys Chem 94:8021–8024

    Article  CAS  Google Scholar 

  44. Case DA, Cheatham TE III, Darden T, Gohlke H, Luo R, Merz KM Jr, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) J Comp Chem 26:1668–1688

    Article  CAS  Google Scholar 

  45. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comp Chem 25:1157–1174

    Article  CAS  Google Scholar 

  46. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) J Comp Phys 103:8577–8593

    CAS  Google Scholar 

  47. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) J Comp Phys 23:327–341

    Article  CAS  Google Scholar 

  48. Humphrey W, Dalke A, Schulten K (1996) J Mol Graph 14:33–38

    Article  CAS  Google Scholar 

  49. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) J Comp Chem 25:1605–1612

    Article  CAS  Google Scholar 

  50. O’Sullivan D, Arrhenius T, Sidney J, Del Guercio MF, Albertson M, Wall M, Oseroff C, Southwood S, Colon SM, Gaeta FC (1991) J Immunol 147:2663–2669

    Google Scholar 

  51. Geluk A, Van Meijgaarden KE, Southwood S, Oseroff C, Drijfhout JW, De Vries RR, Ottenhoff TH, Sette A (1994) J Immunol 152:5742–5748

    CAS  Google Scholar 

  52. Falk K, Rötzschke O, Stevanovíc S, Jung G, Rammensee HG (1994) Immunogenetics 39:230–242

    Article  CAS  Google Scholar 

  53. Vaught A (1996) Linux J 1996:7

    Google Scholar 

  54. Yaneva R, Springer S, Zacharias M (2009) Biopolymers 91:14–27

    Article  CAS  Google Scholar 

  55. Call MJ, Xing X, Cuny GD, Seth NP, Altmann DM, Fugger L, Krogsgaard M, Stein RL, Wucherpfennig KW (2009) J Immunol 182:6342–6352

    Article  CAS  Google Scholar 

  56. Toes REM, Ossendorp F, Offringa R, Melief CJM (1999) J Exp Med 189:753–756

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Authors gratefully acknowledge the valuable technical support provided by Prof. Bernd M. Rode (University of Innsbruck) during this research work. The authors are also grateful to the AMBER supporting team for providing AMBER software. Special thanks to Prof. James Briggs (University of Houston) for his valuable suggestions and proofreading the manuscript.

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Authors and Affiliations

  1. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Zaheer-ul-Haq

  2. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Waqasuddin Khan

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  1. Zaheer-ul-Haq
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Correspondence to Zaheer-ul-Haq.

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Zaheer-ul-Haq, Khan, W. Molecular and structural determinants of adamantyl susceptibility to HLA-DRs allelic variants: an in silico approach to understand the mechanism of MLEs. J Comput Aided Mol Des 25, 81–101 (2011). https://doi.org/10.1007/s10822-010-9404-y

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