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4pe0

From Proteopedia

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Crystal Structure of Calcium-loaded S100B bound to SBi4434

Structural highlights

4pe0 is a 2 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.08Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4pe0"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of Calcium-loaded S100B bound to SBi4434==
-<StructureSection load='4pe0' size='340' side='right' caption='[[4pe0]], [[Resolution|resolution]] 1.08&Aring;' scene=''>
+<StructureSection load='4pe0' size='340' side='right'caption='[[4pe0]], [[Resolution|resolution]] 1.08&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4pe0]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PE0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PE0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4pe0]] 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=4PE0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PE0 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=NQS:2-[(2-HYDROXYETHYL)SULFANYL]NAPHTHALENE-1,4-DIONE'>NQS</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]] 1.08&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pdz|4pdz]], [[4pe1|4pe1]], [[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=NQS:2-[(2-HYDROXYETHYL)SULFANYL]NAPHTHALENE-1,4-DIONE'>NQS</scene></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=4pe0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pe0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4pe0 RCSB], [http://www.ebi.ac.uk/pdbsum/4pe0 PDBsum]</span></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=4pe0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pe0 OCA], [https://pdbe.org/4pe0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pe0 RCSB], [https://www.ebi.ac.uk/pdbsum/4pe0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pe0 ProSAT]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4pe0" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[S100 proteins 3D structures|S100 proteins 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Cavalier, M C]]
+[[Category: Bos taurus]]
-[[Category: Neau, D]]
+[[Category: Large Structures]]
-[[Category: Pierce, P D]]
+[[Category: Cavalier MC]]
-[[Category: Toth, E A]]
+[[Category: Neau D]]
-[[Category: Weber, D J]]
+[[Category: Pierce PD]]
-[[Category: Wilder, P T]]
+[[Category: Toth EA]]
-[[Category: Calcium binding]]
+[[Category: Weber DJ]]
-[[Category: Complex]]
+[[Category: Wilder PT]]
-[[Category: Covalent inhibitor]]
-[[Category: Malignant melanoma]]
-[[Category: Metal binding protein-inhibitor complex]]

4pe0

From Proteopedia

Current revision

Crystal Structure of Calcium-loaded S100B bound to SBi4434

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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