4u6s: Difference between revisions

Revision as of 08:05, 22 March 2023

CtBP1 in complex with substrate phenylpyruvate

Structural highlights

4u6s is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	CA, FMT, NAD, PPY
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CTBP1_HUMAN Involved in controlling the equilibrium between tubular and stacked structures in the Golgi complex. Functions in brown adipose tissue (BAT) differentiation. Corepressor targeting diverse transcription regulators such as GLIS2. Has dehydrogenase activity.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Oncogenic transcriptional coregulators C-terminal Binding Protein (CtBP) 1 and 2 possess regulatory d-isomer specific 2-hydroxyacid dehydrogenase (D2-HDH) domains that provide an attractive target for small molecule intervention. Findings that the CtBP substrate 4-methylthio 2-oxobutyric acid (MTOB) can interfere with CtBP oncogenic activity in cell culture and in mice confirm that such inhibitors could have therapeutic benefit. Recent crystal structures of CtBP 1 and 2 revealed that MTOB binds in an active site containing a dominant tryptophan and a hydrophilic cavity, neither of which are present in other D2-HDH family members. Here, we demonstrate the effectiveness of exploiting these active site features for the design of high affinity inhibitors. Crystal structures of two such compounds, phenylpyruvate (PPy) and 2-hydroxyimino-3-phenylpropanoic acid (HIPP), show binding with favorable ring stacking against the CtBP active site tryptophan and alternate modes of stabilizing the carboxylic acid moiety. Moreover, ITC experiments show that HIPP binds to CtBP with an affinity greater than 1000-fold over that of MTOB, and enzymatic assays confirm that HIPP substantially inhibits CtBP catalysis. These results, thus, provide an important step, and additional insights, for the development of highly selective antineoplastic CtBP inhibitors.

Structure-Guided Design of a High Affinity Inhibitor to Human CtBP.,Hilbert BJ, Morris BL, Ellis KC, Paulsen JL, Schiffer CA, Grossman SR, Royer WE Jr ACS Chem Biol. 2015 Jan 30. PMID:25636004^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sewalt RG, Gunster MJ, van der Vlag J, Satijn DP, Otte AP. C-Terminal binding protein is a transcriptional repressor that interacts with a specific class of vertebrate Polycomb proteins. Mol Cell Biol. 1999 Jan;19(1):777-87. PMID:9858600
↑ Alpatov R, Munguba GC, Caton P, Joo JH, Shi Y, Shi Y, Hunt ME, Sugrue SP. Nuclear speckle-associated protein Pnn/DRS binds to the transcriptional corepressor CtBP and relieves CtBP-mediated repression of the E-cadherin gene. Mol Cell Biol. 2004 Dec;24(23):10223-35. PMID:15542832 doi:https://dx.doi.org/10.1128/MCB.24.23.10223-10235.2004
↑ Purbey PK, Singh S, Notani D, Kumar PP, Limaye AS, Galande S. Acetylation-dependent interaction of SATB1 and CtBP1 mediates transcriptional repression by SATB1. Mol Cell Biol. 2009 Mar;29(5):1321-37. doi: 10.1128/MCB.00822-08. Epub 2008 Dec, 22. PMID:19103759 doi:10.1128/MCB.00822-08
↑ Kumar V, Carlson JE, Ohgi KA, Edwards TA, Rose DW, Escalante CR, Rosenfeld MG, Aggarwal AK. Transcription corepressor CtBP is an NAD(+)-regulated dehydrogenase. Mol Cell. 2002 Oct;10(4):857-69. PMID:12419229
↑ Hilbert BJ, Morris BL, Ellis KC, Paulsen JL, Schiffer CA, Grossman SR, Royer WE Jr. Structure-Guided Design of a High Affinity Inhibitor to Human CtBP. ACS Chem Biol. 2015 Jan 30. PMID:25636004 doi:https://dx.doi.org/10.1021/cb500820b

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Sewalt RG, Gunster MJ, van der Vlag J, Satijn DP, Otte AP. C-Terminal binding protein is a transcriptional repressor that interacts with a specific class of vertebrate Polycomb proteins. Mol Cell Biol. 1999 Jan;19(1):777-87. PMID:9858600

[2] Alpatov R, Munguba GC, Caton P, Joo JH, Shi Y, Shi Y, Hunt ME, Sugrue SP. Nuclear speckle-associated protein Pnn/DRS binds to the transcriptional corepressor CtBP and relieves CtBP-mediated repression of the E-cadherin gene. Mol Cell Biol. 2004 Dec;24(23):10223-35. PMID:15542832 doi:https://dx.doi.org/10.1128/MCB.24.23.10223-10235.2004

[3] Purbey PK, Singh S, Notani D, Kumar PP, Limaye AS, Galande S. Acetylation-dependent interaction of SATB1 and CtBP1 mediates transcriptional repression by SATB1. Mol Cell Biol. 2009 Mar;29(5):1321-37. doi: 10.1128/MCB.00822-08. Epub 2008 Dec, 22. PMID:19103759 doi:10.1128/MCB.00822-08

[4] Kumar V, Carlson JE, Ohgi KA, Edwards TA, Rose DW, Escalante CR, Rosenfeld MG, Aggarwal AK. Transcription corepressor CtBP is an NAD(+)-regulated dehydrogenase. Mol Cell. 2002 Oct;10(4):857-69. PMID:12419229

[5] Hilbert BJ, Morris BL, Ellis KC, Paulsen JL, Schiffer CA, Grossman SR, Royer WE Jr. Structure-Guided Design of a High Affinity Inhibitor to Human CtBP. ACS Chem Biol. 2015 Jan 30. PMID:25636004 doi:https://dx.doi.org/10.1021/cb500820b

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@@ Line 3: / Line 3: @@
 <StructureSection load='4u6s' size='340' side='right'caption='[[4u6s]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4u6s]] 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=4U6S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4U6S FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4u6s]] 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=4U6S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4U6S 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=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PPY:3-PHENYLPYRUVIC+ACID'>PPY</scene></td></tr>
+</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=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PPY:3-PHENYLPYRUVIC+ACID'>PPY</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4u6q|4u6q]], [[4lce|4lce]]</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=4u6s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u6s OCA], [https://pdbe.org/4u6s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4u6s RCSB], [https://www.ebi.ac.uk/pdbsum/4u6s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4u6s ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTBP1, CTBP ([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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4u6s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u6s OCA], [http://pdbe.org/4u6s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4u6s RCSB], [http://www.ebi.ac.uk/pdbsum/4u6s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4u6s ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/CTBP1_HUMAN CTBP1_HUMAN]] Involved in controlling the equilibrium between tubular and stacked structures in the Golgi complex. Functions in brown adipose tissue (BAT) differentiation. Corepressor targeting diverse transcription regulators such as GLIS2. Has dehydrogenase activity.<ref>PMID:9858600</ref> <ref>PMID:15542832</ref> <ref>PMID:19103759</ref> <ref>PMID:12419229</ref>
+[https://www.uniprot.org/uniprot/CTBP1_HUMAN CTBP1_HUMAN] Involved in controlling the equilibrium between tubular and stacked structures in the Golgi complex. Functions in brown adipose tissue (BAT) differentiation. Corepressor targeting diverse transcription regulators such as GLIS2. Has dehydrogenase activity.<ref>PMID:9858600</ref> <ref>PMID:15542832</ref> <ref>PMID:19103759</ref> <ref>PMID:12419229</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Ellis, K C]]
+[[Category: Ellis KC]]
-[[Category: Grossman, S R]]
+[[Category: Grossman SR]]
-[[Category: Hilbert, B J]]
+[[Category: Hilbert BJ]]
-[[Category: Morris, B L]]
+[[Category: Morris BL]]
-[[Category: Paulsen, J L]]
+[[Category: Paulsen JL]]
-[[Category: Royer, W E]]
+[[Category: Royer Jr WE]]
-[[Category: Schiffer, C A]]
+[[Category: Schiffer CA]]
-[[Category: Cancer]]
-[[Category: Oxidoreductase]]
-[[Category: Rossmann fold]]
-[[Category: Substrate]]
-[[Category: Transcription regulator]]

4u6s: Difference between revisions

Revision as of 08:05, 22 March 2023

CtBP1 in complex with substrate phenylpyruvate

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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