3LK0

X-ray structure of bovine SC0067,Ca(2+)-S100B

Summary for 3LK0

• Entry DOI: 10.2210/pdb3lk0/pdb
• Related: 3LK1
• Descriptor: Protein S100-B, CALCIUM ION, 3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethylpropan-1-amine, ... (4 entities in total)
• Functional Keywords: ef hand, alpha helical, metal-binding, metal binding protein
• Biological source: Bos taurus (bovine)
• Cellular location: Cytoplasm: P02638
• Total number of polymer chains: 4
• Total formula weight: 42617.20

Authors

Charpentier, T.H.,Weber, D.J.,Wilder, P.W. (deposition date: 2010-01-26, release date: 2010-12-29, Last modification date: 2024-05-22)

Primary citation

Wilder, P.T.,Charpentier, T.H.,Liriano, M.A.,Gianni, K.,Varney, K.M.,Pozharski, E.,Coop, A.,Toth, E.A.,Mackerell, A.D.,Weber, D.J.
In vitro screening and structural characterization of inhibitors of the S100B-p53 interaction.
Int J High Throughput Screen, 2010:109-126, 2010

PubMed Abstract: 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.

PubMed: 21132089
DOI: 10.2147/IJHTS.S8210

Experimental method

X-RAY DIFFRACTION (2.04 Å)