Intrinsically disordered proteins : drug development and the most interesting examples
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Transcript of Intrinsically disordered proteins : drug development and the most interesting examples
Intrinsically disordered proteins:
drug development and the most interesting examples
Peter Tompa
Institute of EnzymologyHungarian Academy of Sciences
Budapest, Hungary
• IDPsIDPs:: in vitroin vitro evidence andevidence and in vivoin vivo considerationsconsiderations
• nnotot RC RC, tran, transient ordersient order
• ffuncunctional advantagestional advantages (specifi (specificity without city without excessive excessive binding strengthbinding strength, , fast bindingfast binding, , one-one-to-many to-many signalingsignaling))
• prevalentprevalent, , frequency increases from frequency increases from prokaryotes to prokaryotes to eukareukaryotesyotes
• funfunctional importancectional importance (regulatory, (regulatory, transcription, transcription, cytoskeletalcytoskeletal))
• involvement in diseaseinvolvement in disease (cancer-associated, (cancer-associated, neurodegenerative)neurodegenerative)
IUPs
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
Dosztányi (2005) J. Mol. Biol. 347, 827
TAD DBD TD RD AAPPVAPAPAAPTPAAPAPAP
AAPPVAPAPAAPTPAAPAPAP
p53
p53 binding partners (MoRE, SLM)
Oldfield et al. (2005) Biochemistry 44, 12454
MDM2
DNA
S100B
p53
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
PDBSwissProt
signalinghuman cancer
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 small-molecule antagonists of
MDM2
Vassilev et al. (2004) Science 303, 844
PEVPPVRVPEVPKEVVPEKKVPAAPPKKPEVTPVKVPEAPKEVVPEKK
PEVK domain of titin: entropic spring
cytoskeleton
MTs
Tubulin dimers
PKA RII
MAP2: entropic bristle
Mukhopadhyay (2001) FEBS Lett 505, 374
MAP2: entropic bristle
“Dynamic” spacing of MTs in axons and dendrites
Ca2+ + PO4
3-
Ca3(PO4)
2
Casein: scavenger in milk
FlgM: disorder in vivo
Plaxco and Gross (1997) Nature, 386, 657
Plaxco and Gross (1997) Nature, 386, 657
FlgM: disorder in vivo
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
C y cA
C d k 2
Inhibition of Cdks in cell-cycle regulation
Structural ensemble of p27 KID (NMR, MD)
Sivakolundu et al. (2005) JMB 353, 1118
Lacy et al. (2005) NSMB 11, 358
P27 KID binding: molecular staple mechanism
Sheaff et al. (2000) Mol. Cell. 5, 403
p21 turnover w/o ubiquitination
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 The securin storystory
normal chromosome segregation
Inhibition of separase expression
Waizenegger (2002) Curr. Biol. 12, 1368
The securin The securin storystory
Jallepalli (2001) Cell 105, 445
- securin knockout -
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 Entropic gating in nuclear porepore
Patel (2007) Cell 129, 83
...SVFSFSQPGFSSVPAFGQPASSTPTSTSGSVFGAASSTSSSSSFSFGQSSPNTGGGLFGQSNAPAFGQSPGFGQGGSVFGGTSAATTTAATSGFSFCQASGFGSSNTGSVFGQAASTGGIVFGQQSSSSSGSVFGSGNTGRGGGFFSGLGGKPSQDAANKNPFSSASGGFGSTATSNTSNLFGNSGAKTFGGFASSSFGEQKPTGTFSSGGGSVASQGFGFSSPNKTGGFGAAPVFGSPPTFGGSPGFGGVPAFGSAPAFTSPLGSTGGKVFGEGTAAASAGGFGFGSSSNTTSFGTLASQNAPTFGSLSQQTSGFGTQSSGFSGFGSGTGGFSFGSNNSSVQGFGGWRS
350 AAsF: 13% G: 23%S+T: 31%
Long-range repulsion and entropic exclusion
Lim (2006) PNAS 103, 9512
CREB-binding protein (CBP)
Dyson and Wright (2005) Nat. Rev. MCB 6, 197
Histone acetyl
transferase
Transcriptional adaptor
zinc finger 1 Plant homeodom
ain
Nuclear receptor
co-activator binding
Nuclear receptor interactio
nZinc
binding domain
CBP KIX-CREB KID
Dyson and Wright (2005) Nat. Rev. MCB 6, 197
Dyson and Wright (2005) Nat. Rev. MCB 6, 197
CBP TAZ1-HIF1a/CITED2
HIF1: 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