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Intrinsically disordered proteins: drug development and the most interesting examples Peter Tompa Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary IUPs • IDPs: in vitro evidence and in vivo considerations • 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) 1) Involvement in disease and drug development 2) Most interesting examples p53 tumor supressor Levine (1997) Cell 88, 323 Prediction of disorder: IUPred http://iupred.enzim.hu p53 TAD DBD TD RD AAPPVAPAPAAPTPAAPAPAP AAPPVAPAPAAPTPAAPAPAP Dosztányi (2005) J. Mol. Biol. 347, 827 p53 binding partners (MoRE, SLM) DNA p53 MDM2 S100B Oldfield et al. (2005) Biochemistry 44, 12454 p53 binding DNA Breast cancer-associated BRCA1: intrinsic disorder Mark et al. (2005) JMB 345, 275 BRCA1: intrinsic disorder Mark et al. (2005) JMB 345, 275 human cancer signaling SwissProt PDB New molecules approved by FDA Partners of MoRFs: druggable targets Inhibition of p53-MDM2 interaction by small-molecule antagonists Vassilev et al. (2004) Science 303, 844 In vivo activation of p53 by smallmolecule antagonists of MDM2 Vassilev et al. (2004) Science 303, 844 PEVPPVRVPEVPKEVV PEKKVPAAPPKKPEVT PVKVPEAPKEVVPEKK PEVK domain of titin: entropic spring MAP2: entropic bristle cytoskeleton Tubulin dimers MTs PKA RII MAP2: entropic bristle Mukhopadhyay (2001) FEBS Lett 505, 374 “Dynamic” spacing of MTs in axons and dendrites Casein: scavenger in milk Ca2+ + PO43- Ca3(PO4)2 FlgM: disorder in vivo Plaxco and Gross (1997) Nature, 386, 657 FlgM: disorder in vivo Plaxco and Gross (1997) Nature, 386, 657 NMR secondary chemical shifts: transient ordering in FlgM Daughdrill et al. (2004) Biochemistry 37, 1082 FlgM-s28 structure Sorensen et al. (2004) Mol. Cell 14, 127 Inhibition of Cdks in cell-cycle regulation Cdk2 CycA Structural ensemble of p27 KID (NMR, MD) Sivakolundu et al. (2005) JMB 353, 1118 P27 KID binding: molecular staple mechanism Lacy et al. (2005) NSMB 11, 358 p21 turnover w/o ubiquitination Sheaff et al. (2000) Mol. Cell. 5, 403 Proteasomal degradation requires unstructured initiation site Prakash et al. (2000) NSB 11, 830 Endoproteolytic activity of proteasome Liu et al. (2003) Science 299, 408 Mitosis The securin story normal chromosome segregation Inhibition of separase expression Waizenegger (2002) Curr. Biol. 12, 1368 The securin story - securin knockout - Jallepalli (2001) Cell 105, 445 Human full-length securin is IDP Sánchez-Puig et al. (2005) Prot. Sci. 14, 1410 Separase-securin complex by cryoEM Viadiu et al. (2005) NSMB 12, 552 Separase-securin complex reconstruction Viadiu et al. (2005) NSMB 12, 552 Entropic gating in nuclear pore Patel (2007) Cell 129, 83 ...SVFSFSQPGFSSVPAFGQPASSTPTSTSGSVFGAASSTSSSS SFSFGQSSPNTGGGLFGQSNAPAFGQSPGFGQGGSVFGGTSAATT 350 AAs TAATSGFSFCQASGFGSSNTGSVFGQAASTGGIVFGQQSSSSSGS F: 13% VFGSGNTGRGGGFFSGLGGKPSQDAANKNPFSSASGGFGSTATSN G: 23% TSNLFGNSGAKTFGGFASSSFGEQKPTGTFSSGGGSVASQGFGFS SPNKTGGFGAAPVFGSPPTFGGSPGFGGVPAFGSAPAFTSPLGST S+T: 31% GGKVFGEGTAAASAGGFGFGSSSNTTSFGTLASQNAPTFGSLSQQ TSGFGTQSSGFSGFGSGTGGFSFGSNNSSVQGFGGWRS Long-range repulsion and entropic exclusion Lim (2006) PNAS 103, 9512 CREB-binding protein (CBP) Nuclear receptor Transcriptional Histone interaction adaptor zinc acetyl Plant finger 1 transferase Zinc homeodomain binding domain Nuclear receptor coactivator binding Dyson and Wright (2005) Nat. Rev. MCB 6, 197 CBP KIX-CREB KID Dyson and Wright (2005) Nat. Rev. MCB 6, 197 CBP TAZ1-HIF1a/CITED2 HIF1a: hypoxia factor Dyson and Wright (2005) Nat. Rev. MCB 6, 197 CBP bromo-p53 AcLys Dyson and Wright (2005) Nat. Rev. MCB 6, 197 CBP NCBD-ACTR ACTR: activator for thyroid hormone and retinoid receptor Dyson and Wright (2005) Nat. Rev. MCB 6, 197
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