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| | ==Crystal Structure of Calcium-loaded S100B bound to SC124== | | ==Crystal Structure of Calcium-loaded S100B bound to SC124== |
| - | <StructureSection load='4pe1' size='340' side='right' caption='[[4pe1]], [[Resolution|resolution]] 1.58Å' scene=''> | + | <StructureSection load='4pe1' size='340' side='right'caption='[[4pe1]], [[Resolution|resolution]] 1.58Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4pe1]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PE1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PE1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4pe1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PE1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PE1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.576Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pdz|4pdz]], [[4pe0|4pe0]], [[4pe4|4pe4]], [[4pe7|4pe7]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">S100B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 BOVIN])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4pe1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pe1 OCA], [https://pdbe.org/4pe1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pe1 RCSB], [https://www.ebi.ac.uk/pdbsum/4pe1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pe1 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4pe1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pe1 OCA], [http://pdbe.org/4pe1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pe1 RCSB], [http://www.ebi.ac.uk/pdbsum/4pe1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pe1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/S100B_BOVIN 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).<ref>PMID:14661952</ref> | + | [https://www.uniprot.org/uniprot/S100B_BOVIN 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).<ref>PMID:14661952</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4pe1" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4pe1" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[S100 proteins 3D structures|S100 proteins 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bovin]] | + | [[Category: Bos taurus]] |
| - | [[Category: Cavalier, M C]] | + | [[Category: Large Structures]] |
| - | [[Category: Neau, D]] | + | [[Category: Cavalier MC]] |
| - | [[Category: Pierce, A D]] | + | [[Category: Neau D]] |
| - | [[Category: Toth, E A]] | + | [[Category: Pierce AD]] |
| - | [[Category: Weber, D J]] | + | [[Category: Toth EA]] |
| - | [[Category: Wilder, P T]] | + | [[Category: Weber DJ]] |
| - | [[Category: Calcium binding]] | + | [[Category: Wilder PT]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Covalent inhibitor]]
| + | |
| - | [[Category: Malignant melanoma]]
| + | |
| - | [[Category: Metal binding protein-inhibitor complex]]
| + | |
| 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
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 Ca2+-dependent manner, dissociate the p53 tetramer, and inhibit its tumor suppression functions. Likewise, inhibiting S100B with small interfering RNA (siRNAS100B) 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.
Covalent Small Molecule Inhibitors of Ca-Bound S100B.,Cavalier MC, Pierce AD, Wilder PT, Alasady MJ, Hartman KG, Neau DB, Foley TL, Jadhav A, Maloney DJ, Simeonov A, Toth EA, Weber DJ Biochemistry. 2014 Oct 14. PMID:25268459[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Cavalier MC, Pierce AD, Wilder PT, Alasady MJ, Hartman KG, Neau DB, Foley TL, Jadhav A, Maloney DJ, Simeonov A, Toth EA, Weber DJ. Covalent Small Molecule Inhibitors of Ca-Bound S100B. Biochemistry. 2014 Oct 14. PMID:25268459 doi:http://dx.doi.org/10.1021/bi5005552
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