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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. 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 Peter Tompa Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary
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)
Involvement in disease and drug development • 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) p53 DNA MDM2 S100B Oldfield et al. (2005) Biochemistry 44, 12454
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
Inhibition of p53-MDM2 interaction by small-molecule antagonists Vassilev et al. (2004) Science 303, 844
In vivo activation of p53 by small-molecule antagonists of MDM2 Vassilev et al. (2004) Science 303, 844
MAP2: entropic bristle cytoskeleton Tubulin dimers PKA RII MTs
MAP2: entropic bristle Mukhopadhyay (2001) FEBS Lett 505, 374
Casein: scavenger in milk Ca3(PO4)2 Ca2+ + PO43-
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-s28structure Sorensen et al. (2004) Mol. Cell 14, 127
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
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
Long-range repulsion and entropic exclusion Lim (2006) PNAS 103, 9512
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
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