Structural highlights
Function
[S100B_BOVIN] Weakly binds calcium but binds zinc very tightly-distinct binding sites with different affinities exist for both ions on each monomer. Physiological concentrations of potassium ion antagonize the binding of both divalent cations, especially affecting high-affinity calcium-binding sites. Binds to and initiates the activation of STK38 by releasing autoinhibitory intramolecular interactions within the kinase. Interaction with AGER after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling. Could assist ATAD3A cytoplasmic processing, preventing aggregation and favoring mitochondrial localization (By similarity).[1]
Publication Abstract from PubMed
S100B is highly over-expressed in many cancers, including malignant melanoma. In such cancers, S100B binds wild-type p53 in a calcium-dependent manner, sequestering it, and promoting its degradation, resulting in the loss of p53-dependent tumor suppression activities. Therefore, S100B inhibitors may be able to restore wild-type p53 levels in certain cancers and provide a useful therapeutic strategy. In this regard, an automated and sensitive fluorescence polarization competition assay (FPCA) was developed and optimized to screen rapidly for lead compounds that bind Ca(2+)-loaded S100B and inhibit S100B target complex formation. A screen of 2000 compounds led to the identification of 26 putative S100B low molecular weight inhibitors. The binding of these small molecules to S100B was confirmed by nuclear magnetic resonance spectroscopy, and additional structural information was provided by x-ray crystal structures of several compounds in complexes with S100B. Notably, many of the identified inhibitors function by chemically modifying Cys84 in protein. These results validate the use of high-throughput FPCA to facilitate the identification of compounds that inhibit S100B. These lead compounds will be the subject of future optimization studies with the ultimate goal of developing a drug with therapeutic activity for the treatment of malignant melanoma and/or other cancers with elevated S100B.
In vitro screening and structural characterization of inhibitors of the S100B-p53 interaction.,Wilder PT, Charpentier TH, Liriano MA, Gianni K, Varney KM, Pozharski E, Coop A, Toth EA, Mackerell AD, Weber DJ Int J High Throughput Screen. 2010 Jul 7;2010(1):109-126. PMID:21132089[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bhattacharya S, Large E, Heizmann CW, Hemmings B, Chazin WJ. Structure of the Ca2+/S100B/NDR kinase peptide complex: insights into S100 target specificity and activation of the kinase. Biochemistry. 2003 Dec 16;42(49):14416-26. PMID:14661952 doi:http://dx.doi.org/10.1021/bi035089a
- ↑ Wilder PT, Charpentier TH, Liriano MA, Gianni K, Varney KM, Pozharski E, Coop A, Toth EA, Mackerell AD, Weber DJ. In vitro screening and structural characterization of inhibitors of the S100B-p53 interaction. Int J High Throughput Screen. 2010 Jul 7;2010(1):109-126. PMID:21132089 doi:10.2147/IJHTS.S8210
