4PE1

Crystal Structure of Calcium-loaded S100B bound to SC124

Summary for 4PE1

• Entry DOI: 10.2210/pdb4pe1/pdb
• Related: 4PDZ 4PE0 4PE4 4PE7
• Descriptor: Protein S100-B, DIETHYLCARBAMODITHIOIC ACID, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: malignant melanoma, calcium binding, complex, covalent inhibitor, metal binding protein-inhibitor complex, metal binding protein/inhibitor
• Biological source: Bos taurus (Bovine)
• Total number of polymer chains: 2
• Total formula weight: 21822.82

Authors

Cavalier, M.C.,Pierce, A.D.,Wilder, P.T.,Neau, D.,Toth, E.A.,Weber, D.J. (deposition date: 2014-04-22, release date: 2014-10-15, Last modification date: 2024-10-23)

Primary citation

Cavalier, M.C.,Pierce, A.D.,Wilder, P.T.,Alasady, M.J.,Hartman, K.G.,Neau, D.B.,Foley, T.L.,Jadhav, A.,Maloney, D.J.,Simeonov, A.,Toth, E.A.,Weber, D.J.
Covalent Small Molecule Inhibitors of Ca(2+)-Bound S100B.
Biochemistry, 53:6628-6640, 2014

PubMed Abstract: Elevated levels of the tumor marker S100B are observed in malignant melanoma, and this EF-hand-containing protein was shown to directly bind wild-type (wt) p53 in a Ca(2+)-dependent manner, dissociate the p53 tetramer, and inhibit its tumor suppression functions. Likewise, inhibiting S100B with small interfering RNA (siRNA(S100B)) is sufficient to restore wild-type p53 levels and its downstream gene products and induce the arrest of cell growth and UV-dependent apoptosis in malignant melanoma. Therefore, it is a goal to develop S100B inhibitors (SBiXs) that inhibit the S100B-p53 complex and restore active p53 in this deadly cancer. Using a structure-activity relationship by nuclear magnetic resonance approach (SAR by NMR), three persistent binding pockets are found on S100B, termed sites 1-3. While inhibitors that simultaneously bind sites 2 and 3 are in place, no molecules that simultaneously bind all three persistent sites are available. For this purpose, Cys84 was used in this study as a potential means to bridge sites 1 and 2 because it is located in a small crevice between these two deeper pockets on the protein. Using a fluorescence polarization competition assay, several Cys84-modified S100B complexes were identified and examined further. For five such SBiX-S100B complexes, crystallographic structures confirmed their covalent binding to Cys84 near site 2 and thus present straightforward chemical biology strategies for bridging sites 1 and 3. Importantly, one such compound, SC1982, showed an S100B-dependent death response in assays with WM115 malignant melanoma cells, so it will be particularly useful for the design of SBiX molecules with improved affinity and specificity.

PubMed: 25268459
DOI: 10.1021/bi5005552

Experimental method

X-RAY DIFFRACTION (1.576 Å)