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[[ | ==Crystal structure of human small C-terminal domain phosphatase 1 (Scp1) bound to rabeprazole== | ||
<StructureSection load='3pgl' size='340' side='right' caption='[[3pgl]], [[Resolution|resolution]] 2.35Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3pgl]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PGL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3PGL FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=RZX:2-[(R)-{[4-(3-METHOXYPROPOXY)-3-METHYLPYRIDIN-2-YL]METHYL}SULFINYL]-1H-BENZIMIDAZOLE'>RZX</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3l0b|3l0b]], [[3l0c|3l0c]], [[3l0y|3l0y]], [[2ghq|2ghq]], [[2ght|2ght]], [[1t9z|1t9z]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTDSP1, CTDSP1 or SCP1, NIF3, NLIIF, SCP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphoprotein_phosphatase Phosphoprotein phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.16 3.1.3.16] </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=3pgl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pgl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3pgl RCSB], [http://www.ebi.ac.uk/pdbsum/3pgl PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The unstructured C-terminal domain (CTD) of eukaryotic RNA polymerase II dynamically regulates the process of transcription by recruiting different factors to nascent mRNA through its multiple phosphorylation patterns. A newly discovered class of phosphatases, the human small C-terminal domain phosphatases (Scp's), specifically dephosphorylates phosphorylated Ser(5) (phospho.Ser(5)) of the tandem heptad repeats of the CTD of RNA polymerase II. Scp's also function as transcription regulators that epigenetically silence the expression of specific neuronal genes, whose inactivation leads to neuronal stem cell differentiation. Small molecule inhibitors of Scp's will be valuable for elucidating their mechanism in nervous system development and can possibly offer new strategies to treat diseases related to neurodegeneration. Despite the difficulty in developing selective inhibitors of protein phosphatases, we have recognized a characteristic hydrophobic binding pocket adjacent to the active site in Scp's that may facilitate selective inhibition. In the present study, we successfully identified the first selective lead compound, rabeprazole, for the Scp/TFIIF-interacting CTD phosphatase (Fcp) family. The high-resolution crystal structure of rabeprazole-bound Scp1 showed that the compound indeed binds to the hydrophobic binding pocket. We further confirmed that rabeprazole only targets Scp's but not its close family members Fcp1 and Dullard or bacteriophage lambda Ser/Thr phosphatase. Such specificity may prove important for In Vivo studies since accidental inhibition of Fcp1 or Dullard would result in cell malfunctions and even cell death. | |||
Selective Inactivation of a Human Neuronal Silencing Phosphatase by a Small Molecule Inhibitor.,Zhang M, Cho EJ, Burstein G, Siegel D, Zhang Y ACS Chem Biol. 2011 Feb 24. PMID:21348431<ref>PMID:21348431</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[RNA polymerase|RNA polymerase]] | *[[RNA polymerase|RNA polymerase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Phosphoprotein phosphatase]] | [[Category: Phosphoprotein phosphatase]] | ||
[[Category: Burstein, G | [[Category: Burstein, G]] | ||
[[Category: Cho, E J | [[Category: Cho, E J]] | ||
[[Category: Siegel, D | [[Category: Siegel, D]] | ||
[[Category: Zhang, M | [[Category: Zhang, M]] | ||
[[Category: Zhang, Y | [[Category: Zhang, Y]] | ||
[[Category: Ctd phosphatase]] | [[Category: Ctd phosphatase]] | ||
[[Category: Had family]] | [[Category: Had family]] | ||
Revision as of 15:35, 9 December 2014
Crystal structure of human small C-terminal domain phosphatase 1 (Scp1) bound to rabeprazoleCrystal structure of human small C-terminal domain phosphatase 1 (Scp1) bound to rabeprazole
Structural highlights
Publication Abstract from PubMedThe unstructured C-terminal domain (CTD) of eukaryotic RNA polymerase II dynamically regulates the process of transcription by recruiting different factors to nascent mRNA through its multiple phosphorylation patterns. A newly discovered class of phosphatases, the human small C-terminal domain phosphatases (Scp's), specifically dephosphorylates phosphorylated Ser(5) (phospho.Ser(5)) of the tandem heptad repeats of the CTD of RNA polymerase II. Scp's also function as transcription regulators that epigenetically silence the expression of specific neuronal genes, whose inactivation leads to neuronal stem cell differentiation. Small molecule inhibitors of Scp's will be valuable for elucidating their mechanism in nervous system development and can possibly offer new strategies to treat diseases related to neurodegeneration. Despite the difficulty in developing selective inhibitors of protein phosphatases, we have recognized a characteristic hydrophobic binding pocket adjacent to the active site in Scp's that may facilitate selective inhibition. In the present study, we successfully identified the first selective lead compound, rabeprazole, for the Scp/TFIIF-interacting CTD phosphatase (Fcp) family. The high-resolution crystal structure of rabeprazole-bound Scp1 showed that the compound indeed binds to the hydrophobic binding pocket. We further confirmed that rabeprazole only targets Scp's but not its close family members Fcp1 and Dullard or bacteriophage lambda Ser/Thr phosphatase. Such specificity may prove important for In Vivo studies since accidental inhibition of Fcp1 or Dullard would result in cell malfunctions and even cell death. Selective Inactivation of a Human Neuronal Silencing Phosphatase by a Small Molecule Inhibitor.,Zhang M, Cho EJ, Burstein G, Siegel D, Zhang Y ACS Chem Biol. 2011 Feb 24. PMID:21348431[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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