Skip to main content
SpringerLink
Log in

Protein Complex Production from the Drug Discovery Standpoint

  • Chapter
  • First Online:
Advanced Technologies for Protein Complex Production and Characterization

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 896))

  • 5042 Accesses

Abstract

Small molecule drug discovery critically depends on the availability of meaningful in vitro assays to guide medicinal chemistry programs that are aimed at optimizing drug potency and selectivity. As it becomes increasingly evident, most disease relevant drug targets do not act as a single protein. In the body, they are instead generally found in complex with protein cofactors that are highly relevant for their correct function and regulation. This review highlights selected examples of the increasing trend to use biologically relevant protein complexes for rational drug discovery to reduce costly late phase attritions due to lack of efficacy or toxicity.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alberts B (1998) The cell as a collection of protein machines: preparing the next generation of molecular biologists. Cell 92:291–294

    Article  CAS  PubMed  Google Scholar 

  2. Havugimana PC, Hart GT, Nepusz T, Yang H, Turinsky AL, Li Z, Wang PI, Boutz DR, Fong V, Phanse S, Babu M, Craig SA, Hu P, Wan C, Vlasblom J, Dar VU, Bezginov A, Clark GW, Wu GC, Wodak SJ, Tillier ER, Paccanaro A, Marcotte EM, Emili A (2012) A census of human soluble protein complexes. Cell 150:1068–1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Larance M, Lamond AI (2015) Multidimensional proteomics for cell biology. Nat Rev Mol Cell Biol 16:269–280

    Article  CAS  PubMed  Google Scholar 

  4. Assenberg R, Wan PT, Geisse S, Mayr LM (2013) Advances in recombinant protein expression for use in pharmaceutical research. Curr Opin Struct Biol 23:393–402

    Article  CAS  PubMed  Google Scholar 

  5. Manning G, Whyte DB, Martinez R et al (2002) The protein kinase complement of the human genome. Science 298:1912–1934

    Article  CAS  PubMed  Google Scholar 

  6. Malumbres M (2014) Cyclin-dependent kinases. Genome Biol 15:1–10. doi: 10.1186/gb4184

    Google Scholar 

  7. Echalier A, Endicott JA, Noble MEM (2010) Recent developments in cyclin-dependent kinase biochemical and structural studies. Biochim Biophys Acta 1804:511–519

    Article  CAS  PubMed  Google Scholar 

  8. Jeffrey PD, Russo AA, Polyak K et al (1995) Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature 376:313–320

    Article  CAS  PubMed  Google Scholar 

  9. Russo AA, Jeffrey PD, Pavletich NP (1996) Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat Struct Biol 3:696–700

    Article  CAS  PubMed  Google Scholar 

  10. Day PJ, Cleasby A, Tickle IJ et al (2009) Crystal structure of human CDK4 in complex with a D-type cyclin. Proc Natl Acad Sci U S A 106:4166–4170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schulze-Gahmen U, Kim S-H (2002) Structural basis for CDK6 activation by a virus-encoded cyclin. Nat Struct Biol 9:177–181

    CAS  PubMed  Google Scholar 

  12. Baumli S, Lolli G, Lowe ED et al (2008) The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. EMBO J 27:1907–1918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sken CABO, Farnung L, Hintermair C et al (1AD) The structure and substrate specificity of human Cdk12/Cyclin K. Nat Commun 5:1–14

    Google Scholar 

  14. Grahame Hardie D (2014) AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease. J Intern Med 276:543–559

    Article  CAS  PubMed  Google Scholar 

  15. Rana S, Blowers EC, Natarajan A (2015) Small molecule adenosine 5′-monophosphate activated protein kinase (AMPK) modulators and human diseases. J Med Chem 58:2–29

    Article  CAS  PubMed  Google Scholar 

  16. Neumann D, Woods A, Carling D et al (2003) Mammalian AMP-activated protein kinase: functional, heterotrimeric complexes by co-expression of subunits in Escherichia coli. Protein Expr Purif 30:230–237

    Article  CAS  PubMed  Google Scholar 

  17. Rajamohan F, Harris MS, Frisbie RK et al (2010) Escherichia coli expression, purification and characterization of functional full-length recombinant alpha2beta2gamma3 heterotrimeric complex of human AMP-activated protein kinase. Protein Expr Purif 73:189–197

    Article  CAS  PubMed  Google Scholar 

  18. Xiao B, Sanders MJ, Underwood E et al (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472:230–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Xiao B, Sanders MJ, Carmena D, et al (1AD) Structural basis of AMPK regulation by small molecule activators. Nat Commun 4:1–10

    Google Scholar 

  20. Thorpe LM, Yuzugullu H, Zhao JJ (2015) PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 15:7–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dobbelstein M, Moll U (2014) Targeting tumour-supportive cellular machineries in anticancer drug development. Nat Rev Drug Discov 13:179–196

    Article  CAS  PubMed  Google Scholar 

  22. Huang C-H, Mandelker D, Schmidt-Kittler O et al (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744–1748. doi:10.1126/science.1150799

    Article  CAS  PubMed  Google Scholar 

  23. Hu Q, Klippel A, Muslin AJ et al (1995) Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. Science 268:100–102

    Article  CAS  PubMed  Google Scholar 

  24. Sinnamon RH, McDevitt P, Pietrak BL et al (2010) Baculovirus production of fully-active phosphoinositide 3-kinase alpha as a p85alpha-p110alpha fusion for X-ray crystallographic analysis with ATP competitive enzyme inhibitors. Protein Expr Purif 73:167–176

    Article  CAS  PubMed  Google Scholar 

  25. Berndt A, Miller S, Williams O et al (2010) The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat Chem Biol 6:117–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yoo CB, Jones PA (2006) Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5:37–50

    Article  CAS  PubMed  Google Scholar 

  27. Micelli C, Rastelli G (2015) Histone deacetylases: structural determinants of inhibitor selectivity. Drug Discov Today 20:718–735

    Article  CAS  PubMed  Google Scholar 

  28. Joshi P, Greco TM, Guise AJ et al (2013) The functional interactome landscape of the human histone deacetylase family. Mol Syst Biol 9:1–21

    Google Scholar 

  29. Bantscheff M, Hopf C, Savitski MM et al (2011) Chemoproteomics profiling of HDAC. Nat Biotechnol 29:255–265

    Article  CAS  PubMed  Google Scholar 

  30. Drewes G (2012) Future strategies in epigenetic drug discovery. Drug Discov Today Ther Strateg 9:e121–e127

    Article  Google Scholar 

  31. Millard CJ, Watson PJ, Celardo I et al (2013) Class I HDACs share a common mechanism of regulation by inositol phosphates. Mol Cell 51:57–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Watson PJ, Fairall L, Santos GM, Schwabe JWR (2012) Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature 481:1–7

    Google Scholar 

  33. Stopa N, Krebs JE, Shechter D (2015) The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond. Cell Mol Life Sci 72:2041–2059

    Article  CAS  PubMed  Google Scholar 

  34. Antonysamy S, Bonday Z, Campbell RM et al (2012) Crystal structure of the human PRMT5:MEP50 complex. Proc Natl Acad Sci U S A 109:17960–17965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chan-Penebre E, Kuplast KG, Majer CR et al (2015) A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol 11:432–437

    Article  CAS  PubMed  Google Scholar 

  36. Nalepa G, Rolfe M, Harper JW (2006) Drug discovery in the ubiquitin–proteasome system. Nat Publ Group 5:596–613

    CAS  Google Scholar 

  37. King RW, Finley D (2014) Sculpting the proteome with small molecules. Nat Chem Biol 10:870–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gaczynska M, Osmulski PA (2015) Targeting protein-protein interactions in the proteasome super-assemblies. Curr Top Med Chem 15(20):2056–2067

    Article  CAS  PubMed  Google Scholar 

  39. Gallastegui N, Groll M (2010) The 26S proteasome: assembly and function of a destructive machine. Trends Biochem Sci 35:634–642. doi:10.1016/j.tibs.2010.05.005

    Article  CAS  PubMed  Google Scholar 

  40. Gu ZC, Enenkel C (2014) Proteasome assembly. Cell Mol Life Sci 71:4729–4745

    Article  CAS  PubMed  Google Scholar 

  41. Huber EM, Heinemeyer W, Groll M (2015) Bortezomib-resistant mutant proteasomes: structural and biochemical evaluation with Carfilzomib and ONX 0914. Struct Fold Des 23:407–417

    Article  CAS  Google Scholar 

  42. Harshbarger W, Miller C, Diedrich C, Sacchettini J (2015) Crystal structure of the human 20S proteasome in complex with Carfilzomib. Struct Fold Des 23:418–424

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Crelux GmbH, Am Klopferspitz 19a, D82152, Martinsried, Germany

    Ismail Moarefi

Authors
  1. Ismail Moarefi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ismail Moarefi .

Editor information

Editors and Affiliations

  1. Center for Biological Research, SpanishNationalResearchCouncil(CIB-CSIC), Madrid, Spain

    M. Cristina Vega

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Moarefi, I. (2016). Protein Complex Production from the Drug Discovery Standpoint. In: Vega, M. (eds) Advanced Technologies for Protein Complex Production and Characterization. Advances in Experimental Medicine and Biology, vol 896. Springer, Cham. https://doi.org/10.1007/978-3-319-27216-0_1

Download citation

Publish with us

Policies and ethics

Search

Navigation