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Intrinsically disordered proteins : drug development and the most interesting examples

Intrinsically disordered proteins : drug development and the most interesting examples. Peter Tompa. Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary. IUP s. IDPs : in vitro evidence and in vivo considerations n ot RC , tran sient order

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Intrinsically disordered proteins : drug development and the most interesting examples

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  1. Intrinsically disordered proteins: drug development and the most interesting examples Peter Tompa Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary

  2. IUPs • IDPs:in vitroevidence andin vivoconsiderations • not RC, transient order • functional advantages (specificity without excessive binding strength, fast binding, one-to-many signaling) • prevalent, frequency increases from prokaryotes to eukaryotes • functional importance (regulatory, transcription, cytoskeletal) • involvement in disease (cancer-associated, neurodegenerative)

  3. Involvement in disease and drug development • Most interesting examples

  4. p53 tumor supressor Levine (1997) Cell 88, 323

  5. Prediction of disorder: IUPred http://iupred.enzim.hu p53 TAD DBD TD RD AAPPVAPAPAAPTPAAPAPAP AAPPVAPAPAAPTPAAPAPAP Dosztányi (2005) J. Mol. Biol. 347, 827

  6. p53 binding partners (MoRE, SLM) p53 DNA MDM2 S100B Oldfield et al. (2005) Biochemistry 44, 12454

  7. p53 binding DNA

  8. Breast cancer-associated BRCA1: intrinsic disorder Mark et al. (2005) JMB 345, 275

  9. BRCA1: intrinsic disorder Mark et al. (2005) JMB 345, 275

  10. human cancer signaling SwissProt PDB

  11. New molecules approved by FDA

  12. Partners of MoRFs: druggable targets

  13. Inhibition of p53-MDM2 interaction by small-molecule antagonists Vassilev et al. (2004) Science 303, 844

  14. In vivo activation of p53 by small-molecule antagonists of MDM2 Vassilev et al. (2004) Science 303, 844

  15. PEVPPVRVPEVPKEVVPEKKVPAAPPKKPEVTPVKVPEAPKEVVPEKK

  16. PEVK domain of titin: entropic spring

  17. MAP2: entropic bristle cytoskeleton Tubulin dimers PKA RII MTs

  18. MAP2: entropic bristle Mukhopadhyay (2001) FEBS Lett 505, 374

  19. “Dynamic” spacing of MTs in axons and dendrites

  20. Casein: scavenger in milk Ca3(PO4)2 Ca2+ + PO43-

  21. FlgM: disorder in vivo Plaxco and Gross (1997) Nature, 386, 657

  22. FlgM: disorder in vivo Plaxco and Gross (1997) Nature, 386, 657

  23. NMR secondary chemical shifts: transient ordering in FlgM Daughdrill et al. (2004) Biochemistry 37, 1082

  24. FlgM-s28structure Sorensen et al. (2004) Mol. Cell 14, 127

  25. Inhibition of Cdks in cell-cycle regulation

  26. Structural ensemble of p27 KID (NMR, MD) Sivakolundu et al. (2005) JMB 353, 1118

  27. P27 KID binding: molecular staple mechanism Lacy et al. (2005) NSMB 11, 358

  28. p21 turnover w/o ubiquitination Sheaff et al. (2000) Mol. Cell. 5, 403

  29. Proteasomal degradation requires unstructured initiation site Prakash et al. (2000) NSB 11, 830

  30. Endoproteolytic activity of proteasome Liu et al. (2003) Science 299, 408

  31. Mitosis

  32. The securin story normal chromosome segregation Inhibition of separase expression Waizenegger (2002) Curr. Biol. 12, 1368

  33. The securin story - securin knockout - Jallepalli (2001) Cell 105, 445

  34. Human full-length securin is IDP Sánchez-Puig et al. (2005) Prot. Sci. 14, 1410

  35. Separase-securin complex by cryoEM Viadiu et al. (2005) NSMB 12, 552

  36. Separase-securin complex reconstruction Viadiu et al. (2005) NSMB 12, 552

  37. Entropic gating in nuclear pore Patel (2007) Cell 129, 83

  38. ...SVFSFSQPGFSSVPAFGQPASSTPTSTSGSVFGAASSTSSSSSFSFGQSSPNTGGGLFGQSNAPAFGQSPGFGQGGSVFGGTSAATTTAATSGFSFCQASGFGSSNTGSVFGQAASTGGIVFGQQSSSSSGSVFGSGNTGRGGGFFSGLGGKPSQDAANKNPFSSASGGFGSTATSNTSNLFGNSGAKTFGGFASSSFGEQKPTGTFSSGGGSVASQGFGFSSPNKTGGFGAAPVFGSPPTFGGSPGFGGVPAFGSAPAFTSPLGSTGGKVFGEGTAAASAGGFGFGSSSNTTSFGTLASQNAPTFGSLSQQTSGFGTQSSGFSGFGSGTGGFSFGSNNSSVQGFGGWRS 350 AAs F: 13% G: 23% S+T: 31%

  39. Long-range repulsion and entropic exclusion Lim (2006) PNAS 103, 9512

  40. CREB-binding protein (CBP) Nuclear receptor interaction Nuclear receptor co-activator binding Transcriptional adaptor zinc finger 1 Histone acetyl transferase Plant homeodomain Zinc binding domain Dyson and Wright (2005) Nat. Rev. MCB 6, 197

  41. CBP KIX-CREB KID Dyson and Wright (2005) Nat. Rev. MCB 6, 197

  42. CBP TAZ1-HIF1a/CITED2 HIF1a: hypoxia factor Dyson and Wright (2005) Nat. Rev. MCB 6, 197

  43. CBP bromo-p53 AcLys Dyson and Wright (2005) Nat. Rev. MCB 6, 197

  44. CBP NCBD-ACTR ACTR: activator for thyroid hormone and retinoid receptor Dyson and Wright (2005) Nat. Rev. MCB 6, 197

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