6p38

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Crystal Structure Analysis of TAF1 BromodomainCrystal Structure Analysis of TAF1 Bromodomain

Structural highlights

6p38 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.
Method:X-ray diffraction, Resolution 2.8Å
Ligands:
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

Recent reports have highlighted the dual bromodomains of TAF1 (TAF1(1,2)) as synergistic with BET inhibition in cellular cancer models, engendering interest in TAF/BET polypharmacology. Here, we examine structure activity relationships within the BI-2536 PLK1 kinase inhibitor scaffold, previously reported to bind BRD4. We examine binding by this ligand to TAF1(2) and apply structure guided design strategies to discriminate binding to both the PLK1 kinase and BRD4(1) bromodomain while retaining activity on TAF1(2). Through this effort we discover potent dual inhibitors of TAF1(2)/BRD4(1), as well as biased derivatives showing marked TAF1 selectivity. We resolve X-ray crystallographic data sets to examine the mechanisms of the observed TAF1 selectivity and to provide a resource for further development of this scaffold.

Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold.,Remillard D, Buckley DL, Seo HS, Ferguson FM, Dhe-Paganon S, Bradner JE, Gray NS ACS Med Chem Lett. 2019 Sep 13;10(10):1443-1449. doi:, 10.1021/acsmedchemlett.9b00243. eCollection 2019 Oct 10. PMID:31620231[10]

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

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ Remillard D, Buckley DL, Seo HS, Ferguson FM, Dhe-Paganon S, Bradner JE, Gray NS. Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold. ACS Med Chem Lett. 2019 Sep 13;10(10):1443-1449. doi:, 10.1021/acsmedchemlett.9b00243. eCollection 2019 Oct 10. PMID:31620231 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00243

6p38, resolution 2.80Å

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