4I7D

Siah1 bound to synthetic peptide (ACE)KLRPVAMVRP(PRK)VR

Summary for 4I7D

• Entry DOI: 10.2210/pdb4i7d/pdb
• Related: 1K2F 2A25 2AN6 4I7B 4I7C
• Related PRD ID: PRD_000943
• Descriptor: E3 ubiquitin-protein ligase SIAH1, Protein phyllopod, ZINC ION, ... (5 entities in total)
• Functional Keywords: sina, beta sandwich, zinc finger, ubiquitin ligase, covalent inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: Q8IUQ4; Nucleus: Q27934
• Total number of polymer chains: 4
• Total formula weight: 47604.20

Authors

Santelli, E.,Stebbins, J.L.,Feng, Y.,De, S.K.,Purves, A.,Motamedchaboki, K.,Wu, B.,Ronai, Z.A.,Liddington, R.C.,Pellecchia, M. (deposition date: 2012-11-30, release date: 2013-08-14, Last modification date: 2023-09-20)

Primary citation

Stebbins, J.L.,Santelli, E.,Feng, Y.,De, S.K.,Purves, A.,Motamedchaboki, K.,Wu, B.,Ronai, Z.A.,Liddington, R.C.,Pellecchia, M.
Structure-based design of covalent siah inhibitors.
Chem.Biol., 20:973-982, 2013

PubMed Abstract: The E3 ubiquitin ligase Siah regulates key cellular events that are central to cancer development and progression. A promising route to Siah inhibition is disrupting its interactions with adaptor proteins. However, typical of protein-protein interactions, traditional unbiased approaches to ligand discovery did not produce viable hits against this target, despite considerable effort and a multitude of approaches. Ultimately, a rational structure-based design strategy was successful for the identification of Siah inhibitors in which peptide binding drives specific covalent bond formation with the target. X-ray crystallography, mass spectrometry, and functional data demonstrate that these peptide mimetics are efficient covalent inhibitors of Siah and antagonize Siah-dependent regulation of Erk and Hif signaling in the cell. The proposed strategy may result useful as a general approach to the design of peptide-based inhibitors of other protein-protein interactions.

PubMed: 23891150
DOI: 10.1016/j.chembiol.2013.06.008

Experimental method

X-RAY DIFFRACTION (2.4 Å)