4pe4: Difference between revisions
From Proteopedia
Jump to navigationJump to search
New page: '''Unreleased structure''' The entry 4pe4 is ON HOLD Authors: Cavalier, M.C., Pierce, A.D., Wilder, P.T., Neau, D., Toth, E.A., Weber, D.J. Description: Crystal Structure of Calcium-lo... |
No edit summary |
||
| (8 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Crystal Structure of Calcium-loaded S100B bound to SC1475== | |||
<StructureSection load='4pe4' size='340' side='right'caption='[[4pe4]], [[Resolution|resolution]] 2.18Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4pe4]] 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=4PE4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PE4 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.178Å</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=REV:2,3-DIMETHOXY-5-[(1S)-1-PHENYLPROPYL]BENZENE-1,4-DIOL'>REV</scene></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=4pe4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pe4 OCA], [https://pdbe.org/4pe4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pe4 RCSB], [https://www.ebi.ac.uk/pdbsum/4pe4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pe4 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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;"> | |||
== 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<ref>PMID:25268459</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4pe4" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[S100 proteins 3D structures|S100 proteins 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bos taurus]] | |||
[[Category: Large Structures]] | |||
[[Category: Cavalier MC]] | |||
[[Category: Neau D]] | |||
[[Category: Pierce AD]] | |||
[[Category: Toth EA]] | |||
[[Category: Weber DJ]] | |||
[[Category: Wilder PT]] | |||
