| Structural highlights
5i29 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: | 67B, CA |
| Related: | 5i1q |
| 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
The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.
Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains.,Crawford TD, Tsui V, Flynn EM, Wang S, Taylor AM, Cote A, Audia JE, Beresini MH, Burdick DJ, Cummings R, Dakin LA, Duplessis M, Good AC, Hewitt MC, Huang HR, Jayaram H, Kiefer JR, Jiang Y, Murray J, Nasveschuk CG, Pardo E, Poy F, Romero FA, Tang Y, Wang J, Xu Z, Zawadzke LE, Zhu X, Albrecht BK, Magnuson SR, Bellon S, Cochran AG J Med Chem. 2016 Jun 9;59(11):5391-402. doi: 10.1021/acs.jmedchem.6b00264. Epub, 2016 May 31. PMID:27219867[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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:https://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:https://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
- ↑ Crawford TD, Tsui V, Flynn EM, Wang S, Taylor AM, Cote A, Audia JE, Beresini MH, Burdick DJ, Cummings R, Dakin LA, Duplessis M, Good AC, Hewitt MC, Huang HR, Jayaram H, Kiefer JR, Jiang Y, Murray J, Nasveschuk CG, Pardo E, Poy F, Romero FA, Tang Y, Wang J, Xu Z, Zawadzke LE, Zhu X, Albrecht BK, Magnuson SR, Bellon S, Cochran AG. Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains. J Med Chem. 2016 Jun 9;59(11):5391-402. doi: 10.1021/acs.jmedchem.6b00264. Epub, 2016 May 31. PMID:27219867 doi:https://dx.doi.org/10.1021/acs.jmedchem.6b00264
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