5mg2

From Proteopedia

(Difference between revisions)

Revision as of 07:18, 19 August 2020

Crystal structure of the second bromodomain of human TAF1 in complex with BAY-299 chemical probe

Structural highlights

5mg2 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	TAF1, BA2R, CCG1, CCGS, TAF2A (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[TAF1_HUMAN] Defects in TAF1 are the cause of dystonia type 3 (DYT3) [MIM:314250]; also called X-linked dystonia-parkinsonism (XDP). DYT3 is a X-linked dystonia-parkinsonism disorder. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT3 is characterized by severe progressive torsion dystonia followed by parkinsonism. Its prevalence is high in the Philippines. DYT3 has a well-defined pathology of extensive neuronal loss and mosaic gliosis in the striatum (caudate nucleus and putamen) which appears to resemble that in Huntington disease.^[1] ^[2]

Function

[TAF1_HUMAN] Largest component and core scaffold of the TFIID basal transcription factor complex. Contains novel N- and C-terminal Ser/Thr kinase domains which can autophosphorylate or transphosphorylate other transcription factors. Phosphorylates TP53 on 'Thr-55' which leads to MDM2-mediated degradation of TP53. Phosphorylates GTF2A1 and GTF2F1 on Ser residues. Possesses DNA-binding activity. Essential for progression of the G1 phase of the cell cycle.^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Publication Abstract from PubMed

Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2- or TAF1-histone H3.3 or H4 interaction assay.

Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains.,Bouche L, Christ CD, Siegel S, Fernandez-Montalvan AE, Holton SJ, Fedorov O, Ter Laak A, Sugawara T, Stockigt D, Tallant C, Bennett J, Monteiro O, Diaz-Saez L, Siejka P, Meier J, Putter V, Weiske J, Muller S, Huber KVM, Hartung IV, Haendler B J Med Chem. 2017 May 1. doi: 10.1021/acs.jmedchem.7b00306. PMID:28402630^[10]

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

References

↑ Nolte D, Niemann S, Muller U. Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10347-52. Epub 2003 Aug 19. PMID:12928496 doi:http://dx.doi.org/10.1073/pnas.1831949100
↑ Makino S, Kaji R, Ando S, Tomizawa M, Yasuno K, Goto S, Matsumoto S, Tabuena MD, Maranon E, Dantes M, Lee LV, Ogasawara K, Tooyama I, Akatsu H, Nishimura M, Tamiya G. Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am J Hum Genet. 2007 Mar;80(3):393-406. Epub 2007 Jan 23. PMID:17273961 doi:S0002-9297(07)60089-5
↑ Sekiguchi T, Nohiro Y, Nakamura Y, Hisamoto N, Nishimoto T. The human CCG1 gene, essential for progression of the G1 phase, encodes a 210-kilodalton nuclear DNA-binding protein. Mol Cell Biol. 1991 Jun;11(6):3317-25. PMID:2038334
↑ Hisatake K, Hasegawa S, Takada R, Nakatani Y, Horikoshi M, Roeder RG. The p250 subunit of native TATA box-binding factor TFIID is the cell-cycle regulatory protein CCG1. Nature. 1993 Mar 11;362(6416):179-81. PMID:8450888 doi:http://dx.doi.org/10.1038/362179a0
↑ Dikstein R, Ruppert S, Tjian R. TAFII250 is a bipartite protein kinase that phosphorylates the base transcription factor RAP74. Cell. 1996 Mar 8;84(5):781-90. PMID:8625415
↑ O'Brien T, Tjian R. Functional analysis of the human TAFII250 N-terminal kinase domain. Mol Cell. 1998 May;1(6):905-11. PMID:9660973
↑ Siegert JL, Robbins PD. Rb inhibits the intrinsic kinase activity of TATA-binding protein-associated factor TAFII250. Mol Cell Biol. 1999 Jan;19(1):846-54. PMID:9858607
↑ Solow S, Salunek M, Ryan R, Lieberman PM. Taf(II) 250 phosphorylates human transcription factor IIA on serine residues important for TBP binding and transcription activity. J Biol Chem. 2001 May 11;276(19):15886-92. Epub 2001 Feb 20. PMID:11278496 doi:10.1074/jbc.M009385200
↑ Li HH, Li AG, Sheppard HM, Liu X. Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression. Mol Cell. 2004 Mar 26;13(6):867-78. PMID:15053879
↑ Bouche L, Christ CD, Siegel S, Fernandez-Montalvan AE, Holton SJ, Fedorov O, Ter Laak A, Sugawara T, Stockigt D, Tallant C, Bennett J, Monteiro O, Diaz-Saez L, Siejka P, Meier J, Putter V, Weiske J, Muller S, Huber KVM, Hartung IV, Haendler B. Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains. J Med Chem. 2017 May 1. doi: 10.1021/acs.jmedchem.7b00306. PMID:28402630 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00306

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5mg2"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the second bromodomain of human TAF1 in complex with BAY-299 chemical probe==
-<StructureSection load='5mg2' size='340' side='right' caption='[[5mg2]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
+<StructureSection load='5mg2' size='340' side='right'caption='[[5mg2]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5mg2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MG2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MG2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5mg2]] 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=5MG2 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MG2 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7M8:6-(3-OXIDANYLPROPYL)-2-(1,3,6-TRIMETHYL-2-OXIDANYLIDENE-BENZIMIDAZOL-5-YL)BENZO[DE]ISOQUINOLINE-1,3-DIONE'>7M8</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7M8:6-(3-OXIDANYLPROPYL)-2-(1,3,6-TRIMETHYL-2-OXIDANYLIDENE-BENZIMIDAZOL-5-YL)BENZO[DE]ISOQUINOLINE-1,3-DIONE'>7M8</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=5mg2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mg2 OCA], [http://pdbe.org/5mg2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mg2 RCSB], [http://www.ebi.ac.uk/pdbsum/5mg2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mg2 ProSAT]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TAF1, BA2R, CCG1, CCGS, TAF2A ([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://proteopedia.org/fgij/fg.htm?mol=5mg2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mg2 OCA], [http://pdbe.org/5mg2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mg2 RCSB], [http://www.ebi.ac.uk/pdbsum/5mg2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mg2 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5mg2" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Transcription initiation factors 3D structures|Transcription initiation factors 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Arrowsmith, C H]]
 [[Category: Bouche, L]]

5mg2

From Proteopedia

Revision as of 07:18, 19 August 2020

Crystal structure of the second bromodomain of human TAF1 in complex with BAY-299 chemical probe

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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