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==Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives==
==Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives==
<StructureSection load='3tc5' size='340' side='right' caption='[[3tc5]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
<StructureSection load='3tc5' size='340' side='right'caption='[[3tc5]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3tc5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TC5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TC5 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3tc5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TC5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TC5 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3T5:(11ALPHA,16ALPHA)-9-FLUORO-11,17-DIHYDROXY-16-METHYL-3,20-DIOXOPREGNA-1,4-DIEN-21-YL+DIHYDROGEN+PHOSPHATE'>3T5</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</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]] 1.4&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1pin|1pin]], [[2zr6|2zr6]], [[2itk|2itk]], [[2q5a|2q5a]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3T5:(11ALPHA,16ALPHA)-9-FLUORO-11,17-DIHYDROXY-16-METHYL-3,20-DIOXOPREGNA-1,4-DIEN-21-YL+DIHYDROGEN+PHOSPHATE'>3T5</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIN1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3tc5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tc5 OCA], [https://pdbe.org/3tc5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tc5 RCSB], [https://www.ebi.ac.uk/pdbsum/3tc5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tc5 ProSAT]</span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </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=3tc5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tc5 OCA], [http://pdbe.org/3tc5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3tc5 RCSB], [http://www.ebi.ac.uk/pdbsum/3tc5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3tc5 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/PIN1_HUMAN PIN1_HUMAN]] Essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Catalyzes pSer/Thr-Pro cis/trans isomerizations. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation.<ref>PMID:15664191</ref> <ref>PMID:16644721</ref> <ref>PMID:21497122</ref> 
[https://www.uniprot.org/uniprot/PIN1_HUMAN PIN1_HUMAN] Essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Catalyzes pSer/Thr-Pro cis/trans isomerizations. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation.<ref>PMID:15664191</ref> <ref>PMID:16644721</ref> <ref>PMID:21497122</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Phosphorylation-dependent protein binding domains are crucially important for intracellular signaling pathways and thus highly relevant targets in chemical biology. By screening of chemical libraries against 12 structurally diverse phosphorylation-dependent protein binding domains, we have identified fosfosal and dexamethasone-21-phosphate as selective inhibitors of two antitumor targets: the SH2 domain of the transcription factor STAT5b and the substrate-binding domain of the peptidyl-prolyl isomerase Pin1, respectively. Both compounds are phosphate prodrugs with documented clinical use as anti-inflammatory agents in humans and were discovered with a high hit rate from a small subgroup within the screening library. Our study indicates O-phosphorylation of appropriately preselected natural products or natural product derivatives as a generally applicable strategy for the identification of non-reactive and non-peptidic ligands of phosphorylation-dependent protein binding domains. Moreover, our data indicate that it would be advisable to monitor the bioactivities of clinically used prodrugs in their uncleaved state against phosphorylation-dependent protein binding domains.
 
Selective Targeting of Disease-Relevant Protein Binding Domains by O-Phosphorylated Natural Product Derivatives.,Graber M, Janczyk W, Sperl B, Elumalai N, Kozany C, Hausch F, Holak TA, Berg T ACS Chem Biol. 2011 Aug 10. PMID:21797253<ref>PMID:21797253</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3tc5" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Peptidyl-prolyl cis-trans isomerase|Peptidyl-prolyl cis-trans isomerase]]
*[[Peptidyl-prolyl cis-trans isomerase 3D structures|Peptidyl-prolyl cis-trans isomerase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Peptidylprolyl isomerase]]
[[Category: Large Structures]]
[[Category: Berg, T]]
[[Category: Berg T]]
[[Category: Elumalai, N]]
[[Category: Elumalai N]]
[[Category: Graeber, M]]
[[Category: Graeber M]]
[[Category: Hausch, F]]
[[Category: Hausch F]]
[[Category: Holak, T A]]
[[Category: Holak TA]]
[[Category: Janczyk, W]]
[[Category: Janczyk W]]
[[Category: Kozany, C]]
[[Category: Kozany C]]
[[Category: Sperl, B]]
[[Category: Sperl B]]
[[Category: Cell cycle]]
[[Category: Isomerase-isomerase inhibitor complex]]
[[Category: Nucleus]]
[[Category: Oncogenic transformation]]
[[Category: Phosphoprotein]]
[[Category: Rotamase]]
[[Category: Small molecule]]

Latest revision as of 13:23, 14 March 2024

Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives

3tc5, resolution 1.40Å

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