2vge

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Crystal structure of the C-terminal region of human iASPPCrystal structure of the C-terminal region of human iASPP

Structural highlights

2vge is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.1Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IASPP_HUMAN Regulator that plays a central role in regulation of apoptosis and transcription via its interaction with NF-kappa-B and p53/TP53 proteins. Blocks transcription of HIV-1 virus by inhibiting the action of both NF-kappa-B and SP1. Also inhibits p53/TP53 function, possibly by preventing the association between p53/TP53 and ASPP1 or ASPP2, and therefore suppressing the subsequent activation of apoptosis.[1] [2] [3] [4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

ASPP1 and ASPP2 are activators of p53-dependent apoptosis, whereas iASPP is an inhibitor of p53. Binding assays showed differential binding for C-terminal domains of iASPP and ASPP2 to the core domains of p53 family members p53, p63, and p73. We also determined a high-resolution crystal structure for the C terminus of iASPP, comprised of four ankyrin repeats and an SH3 domain. The crystal lattice revealed an interaction between eight sequential residues in one iASPP molecule and the p53-binding site of a neighboring molecule. ITC confirmed that a peptide corresponding to the crystallographic interaction shows specific binding to iASPP. The contributions of ankyrin repeat residues, in addition to those of the SH3 domain, generate distinctive architecture at the p53-binding site suitable for inhibition by small molecules. These results suggest that the binding properties of iASPP render it a target for antitumor therapeutics and provide a peptide-based template for compound design.

Biochemical and structural studies of ASPP proteins reveal differential binding to p53, p63, and p73.,Robinson RA, Lu X, Jones EY, Siebold C Structure. 2008 Feb;16(2):259-68. PMID:18275817[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Slee EA, Gillotin S, Bergamaschi D, Royer C, Llanos S, Ali S, Jin B, Trigiante G, Lu X. The N-terminus of a novel isoform of human iASPP is required for its cytoplasmic localization. Oncogene. 2004 Dec 2;23(56):9007-16. PMID:15489900 doi:http://dx.doi.org/1208088
  2. ↑ Yang JP, Hori M, Sanda T, Okamoto T. Identification of a novel inhibitor of nuclear factor-kappaB, RelA-associated inhibitor. J Biol Chem. 1999 May 28;274(22):15662-70. PMID:10336463
  3. ↑ Takada N, Sanda T, Okamoto H, Yang JP, Asamitsu K, Sarol L, Kimura G, Uranishi H, Tetsuka T, Okamoto T. RelA-associated inhibitor blocks transcription of human immunodeficiency virus type 1 by inhibiting NF-kappaB and Sp1 actions. J Virol. 2002 Aug;76(16):8019-30. PMID:12134007
  4. ↑ Bergamaschi D, Samuels Y, O'Neil NJ, Trigiante G, Crook T, Hsieh JK, O'Connor DJ, Zhong S, Campargue I, Tomlinson ML, Kuwabara PE, Lu X. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat Genet. 2003 Feb;33(2):162-7. Epub 2003 Jan 13. PMID:12524540 doi:http://dx.doi.org/10.1038/ng1070
  5. ↑ Robinson RA, Lu X, Jones EY, Siebold C. Biochemical and structural studies of ASPP proteins reveal differential binding to p53, p63, and p73. Structure. 2008 Feb;16(2):259-68. PMID:18275817 doi:10.1016/j.str.2007.11.012

2vge, resolution 2.10Å

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