Skip to main content
SpringerLink
Log in

Molecular dynamics analysis of a series of 22 potential farnesyltransferase substrates containing a CaaX-motif

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Protein farnesyltransferase (FTase) is an important target in many research fields, more markedly so in cancer investigation since several proteins known to be involved in human cancer development are thought to serve as substrates for FTase and to require farnesylation for proper biological activity. Several FTase inhibitors (FTIs) have advanced into clinical testing. Nevertheless, despite the progress in the field several functional and mechanistic doubts on the FTase catalytic activity have persisted. This work provides some crucial information on this important enzyme by describing the application of molecular dynamics simulations using specifically designed molecular mechanical parameters for a variety of 22 CaaX peptides known to work as natural substrates or inhibitors for this enzyme. The study involves a comparative analysis of several important molecular aspects, at the mechanistic level, of the behavior of substrates and inhibitors at the dynamic level, including the behavior of the enzyme and peptides, as well as their interaction, together with the effect of the solvent. Properties evaluated include the radial distribution function of the water molecules around the catalytically important zinc metal atom and cysteine sulfur of CaaX, the conformations of the substrate and inhibitor and the corresponding RMSF values, critical hydrogen bonds, and several catalytically relevant distances. These results are discussed in light of recent experimental and computational evidence that provides new insights into the activity of this enzyme.

A Dynamic portrait on the interaction of 22 CaaX FTase peptides is traced offering an integrated view on the structural determinants associated with FTase-peptide binding

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Chen WJ, Andres DA, Goldstein JL, Russell DW, Brown MS (1991) Cell 66:327–334

    Article  CAS  Google Scholar 

  2. Chen WJ, Andres DA, Goldstein JL, Brown MS (1991) Proc Natl Acad Sci USA 88:11368–11372

    Article  CAS  Google Scholar 

  3. Reiss Y, Goldstein JL, Seabra MC, Casey PJ, Brown MS (1990) Cell 62:81–88

    Article  CAS  Google Scholar 

  4. Reiss Y, Seabra MC, Armstrong SA, Slaughter CA, Goldstein JL, Brown MS (1991) J Biol Chem 266:10672–10677

    CAS  Google Scholar 

  5. Sousa SF, Fernandes PA, Ramos MJ (2005) J Biol Inorg Chem 10:3–10

    Article  CAS  Google Scholar 

  6. Chen WJ, Moomaw JF, Overton L, Kost TA, Casey PJ (1993) J Biol Chem 268:9675–9680

    CAS  Google Scholar 

  7. Reiss Y, Brown MS, Goldstein JL (1992) J Biol Chem 267:6403–6408

    CAS  Google Scholar 

  8. Moores SL, Schaber MD, Mosser SD, Rands E, O’Hara MB, Garsky VM, Marshall MS, Pompliano DL, Gibbs JB (1991) J Biol Chem 266:14603–14610

    CAS  Google Scholar 

  9. Casey PJ, Seabra MC (1996) J Biol Chem 271:5289–5292

    Article  CAS  Google Scholar 

  10. Hancock JF, Magee AI, Childs JE, Marshall CJ (1989) Cell 57:1167–1177

    Article  CAS  Google Scholar 

  11. Jackson JH, Cochrane CG, Bourne JR, Solski PA, Buss JE, Der CJ (1990) Proc Natl Acad Sci USA 87:3042–3046

    Article  CAS  Google Scholar 

  12. Kato K, Cox AD, Hisaka MM, Graham SM, Buss JE, Der CJ (1992) Proc Natl Acad Sci USA 89:6403–6407

    Article  CAS  Google Scholar 

  13. Dolence JM, Poulter CD (1995) Proc Natl Acad Sci USA 92:5008–5011

    Article  CAS  Google Scholar 

  14. Takai Y, Sasaki T, Matozaki T (2001) Physiol Rev 81:153–208

    CAS  Google Scholar 

  15. Barbacid M (1987) Annu Rev Biochem 56:779–827

    Article  CAS  Google Scholar 

  16. Bos JL (1989) Cancer Res 49:4682–4689

    CAS  Google Scholar 

  17. Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, van Boom JH, van der Eb AJ, Vogelstein B (1987) Nature 327:293–297

    Article  CAS  Google Scholar 

  18. Vogelstein B, Fearon ER, Hamilton AD, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL (1988) New Engl J Med 319:525–532

    Article  CAS  Google Scholar 

  19. Wallace A, Koblan KS, Hamilton K, Marquis-Omer DJ, Miller PJ, Mosser SD, Omer CA, Schaber MD, Cortese R, Oliff A, Gibbs JB, Pessi A (1996) J Biol Chem 271:31306

    Article  CAS  Google Scholar 

  20. Sousa SF, Fernandes PA, Ramos MJ (2008) Curr Med Chem 15:1478–1492

    Article  CAS  Google Scholar 

  21. Pan J, Yeung SCJ (2005) Cancer Res 65:9109–9112

    Article  CAS  Google Scholar 

  22. Agrawal AG, Somani RR (2009) Min Rev Med Chem 9:638–652

    Article  CAS  Google Scholar 

  23. Berndt N, Hamilton AD, Sebti SM (2011) Nat Rev Cancer 11:775–791

    Article  CAS  Google Scholar 

  24. Tsimberidou AM, Chandhasin C, Kurzrock R (2010) Exp Opin Invest Drugs 19:1569–1580

    Article  CAS  Google Scholar 

  25. Rao S, Cunningham D, de Gramont A, Scheithauer W, Smakal M, Humblet Y, Kourteva G, Iveson T, Andre T, Dostalova J, Illes A, Belly R, Perez-Ruixo JJ, Park YC, Palmer PA (2004) J Clin Oncol 22:3950–3957

    Article  CAS  Google Scholar 

  26. Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, Schoffski P, Post S, Verslype C, Neumann H, Safran H, Humblet Y, Perez Ruixo J, Ma Y, von Hoff D (2004) J Clin Oncol 22:1430–1438

    Article  Google Scholar 

  27. Zhang FL, Kirschmeier P, Carr D, James L, Bond RW, Wang L, Patton R, Windsor WT, Syto R, Zhang R, Bishop WR (1997) J Biol Chem 272:10232–10239

    Article  CAS  Google Scholar 

  28. Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ, Bishop WR, Pai JK (1997) J Biol Chem 272:14459–14464

    Article  CAS  Google Scholar 

  29. Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM (1997) J Biol Chem 272:14093–14097

    Article  CAS  Google Scholar 

  30. Tucker TJ, Abrams MT, Buser CA, Davide JP, Ellis-Hutchings M, Fernandes C, Gibbs JB, Graham SL, Hartman GD, Huber HE, Liu D, Lobell RB, Lumma WC, Robinson RG, Sisko JT, Smith AM (2002) Bioorg Med Chem Lett 12:2027–2030

    Article  CAS  Google Scholar 

  31. Moorthy NSHN, Sousa SF, Ramos MJ, Fernandes PA (2011) J Enzyme Inhib Med Chem 26:777–791

    Article  CAS  Google Scholar 

  32. Moorthy NSHN, Sousa SF, Ramos MJ, Fernandes PA (2011) J Biomol Screen 16:1037–1046

    Article  CAS  Google Scholar 

  33. Perez MAS, Sousa SF, Oliveira EFT, Fernandes PA, Ramos MJ (2011) J Phys Chem B 115:15339–15354

    Article  CAS  Google Scholar 

  34. Long SB, Casey PJ, Beese LS (2000) Struct Fold Des 8:209–222

    Article  CAS  Google Scholar 

  35. Reid TS, Terry KL, Casey PJ, Beese LS (2004) J Mol Biol 343:417–433

    Article  CAS  Google Scholar 

  36. Long SB, Hancock PJ, Kral AM, Hellinga HW, Beese LS (2001) Proc Natl Acad Sci USA 98:12948–12953

    Article  CAS  Google Scholar 

  37. Sousa SF, Fernandes PA, Ramos MJ (2005) Biophys J 88:483–494

    Article  CAS  Google Scholar 

  38. Sousa SF, Fernandes PA, Ramos MJ (2007) J Comput Chem 28:1160–1168

    Article  CAS  Google Scholar 

  39. Tamames B, Sousa SF, Tamames J, Fernandes PA, Ramos MJ (2007) Proteins 69:466–475

    Article  CAS  Google Scholar 

  40. Park HW, Boduluri SR, Moomaw JF, Casey PJ, Beese LS (1997) Science 275:1800–1804

    Article  CAS  Google Scholar 

  41. Long SB, Casey PJ, Beese LS (2002) Nature 419:645–650

    Article  CAS  Google Scholar 

  42. Tobin DA, Pickett JS, Hartman HL, Fierke CA, Penner-Hahn JE (2003) J Am Chem Soc 125:9962–9969

    Article  CAS  Google Scholar 

  43. Pickett JS, Bowers KE, Fierke CA (2003) J Biol Chem 278:51243–51250

    Article  CAS  Google Scholar 

  44. Bowers KE, Fierke CA (2004) Biochemistry 43:5256–5265

    Article  CAS  Google Scholar 

  45. Pickett JS, Bowers KE, Hartman HL, Fu HW, Embry AC, Casey PJ, Fierke CA (2003) Biochemistry 42:9741–9748

    Article  CAS  Google Scholar 

  46. Hartman HL, Bowers KE, Fierke CA (2004) J Biol Chem 279:30546–30553

    Article  CAS  Google Scholar 

  47. Ho MH, De Vivo M, Dal Peraro M, Klein ML (2009) J Chem Theor Comput 5:1657–1666

    Article  CAS  Google Scholar 

  48. Cui G, Merz KM (2007) Biochemistry 46:12375–12381

    Article  CAS  Google Scholar 

  49. Sousa SF, Fernandes PA, Ramos MJ (2007) Theor Chem Acc 117:171–181

    Article  CAS  Google Scholar 

  50. Sousa SF, Fernandes PA, Ramos MJ (2009) Bioorg Med Chem 17:3369–3378

    Article  CAS  Google Scholar 

  51. Sousa SF, Fernandes PA, Ramos MJ (2008) Int J Quant Chem 108:1939–1950

    Article  CAS  Google Scholar 

  52. Sousa SF, Fernandes PA, Ramos MJ (2008) J Phys Chem B 112:8681–8691

    Article  CAS  Google Scholar 

  53. Sousa SF, Fernandes PA, Ramos MJ (2007) Proteins 66:205–218

    Article  CAS  Google Scholar 

  54. Mirza UA, Chen GD, Liu YH, Doll RJ, Girijavallabhan VM, Ganguly AK, Pramanik BN (2008) J Mass Spectrom 43:1393–1401

    Article  CAS  Google Scholar 

  55. Sousa SF, Fernandes PA, Ramos MJ (2005) J Mol Struct (THEOCHEM) 729:125–129

    Article  CAS  Google Scholar 

  56. Sousa SF, Fernandes PA, Ramos MJ (2009) Chemistry 15:4243–4247

    Article  CAS  Google Scholar 

  57. Sousa SF, Fernandes PA, Ramos MJ (2007) J Am Chem Soc 129:1378–1385

    Article  CAS  Google Scholar 

  58. Rardin RL, Tolman WB, Lippard SJ (1991) New J Chem 15:417–430

    CAS  Google Scholar 

  59. Goldstein JL, Brown MS, Stradley SJ, Reiss Y, Gierasch LM (1991) J Biol Chem 266:15575–15578

    CAS  Google Scholar 

  60. Reiss Y, Stradley SJ, Gierasch LM, Brown MS, Goldstein JL (1991) Proc Natl Acad Sci USA 88:732–736

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank the financial support provided by Fundação para a Ciência e a Tecnologia (FCT) (PTDC/QUI-QUI/103118/2008 and grant no. Pest-C/EQB/LA0006/2011).

Author information

Authors and Affiliations

  1. REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, s/n, 4169-007, Porto, Portugal

    Sérgio F. Sousa, João T. S. Coimbra, Diogo Paramos, Rita Pinto, Rodrigo S. Guimarães, Vitor Teixeira, Pedro A. Fernandes & Maria J. Ramos

Authors
  1. Sérgio F. Sousa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. João T. S. Coimbra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diogo Paramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rita Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rodrigo S. Guimarães
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vitor Teixeira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pedro A. Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maria J. Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sérgio F. Sousa.

Electronic supplementary material

Below is the link to the electronic supplementary material.

894_2012_1590_MOESM1_ESM.doc

Schematic representation of the typical average conformations adopted for the different tetrapeptides at the active-site listing the tetrapeptides adopting a productive and a non-productive thiolate conformation. (DOC 543 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sousa, S.F., Coimbra, J.T.S., Paramos, D. et al. Molecular dynamics analysis of a series of 22 potential farnesyltransferase substrates containing a CaaX-motif. J Mol Model 19, 673–688 (2013). https://doi.org/10.1007/s00894-012-1590-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-012-1590-1

Keywords

Search

Navigation