7l6x

From Proteopedia
Jump to navigation Jump to search

Crystal structure of the tandem bromodomain (BD1, BD2) of human TAF1 bound to GNE-371Crystal structure of the tandem bromodomain (BD1, BD2) of human TAF1 bound to GNE-371

Structural highlights

7l6x 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 2.75Å
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

Bromodomains regulate chromatin remodeling and gene transcription through recognition of acetylated lysines on histones and other proteins. Bromodomain-containing protein TAF1, a subunit of general transcription factor TFIID, initiates preinitiation complex formation and cellular transcription. TAF1 serves as a cofactor for certain oncogenic transcription factors and is implicated in regulating the p53 tumor suppressor. Therefore, TAF1 is a potential target to develop small molecule therapeutics for diseases arising from dysregulated transcription, such as cancer. Here, we report the ATR kinase inhibitor AZD6738 (Ceralasertib) and analogues thereof as bona fide inhibitors of TAF1. Crystallographic and small-angle X-ray scattering studies established that newly identified and previously reported inhibitors stabilize distinct structural states of the TAF1 tandem bromodomain through "open-closed" transitions and dimerization. Combined with functional studies on p53 signaling in cancer cell lines, the data provide new insights into the feasibility and challenges of TAF1 inhibitors as chemical probes and therapeutics.

Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain.,Karim RM, Yang L, Chen L, Bikowitz MJ, Lu J, Grassie D, Shultz ZP, Lopchuk JM, Chen J, Schonbrunn E J Med Chem. 2022 Feb 22. doi: 10.1021/acs.jmedchem.1c01999. PMID:35191694[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. ↑ Karim RM, Yang L, Chen L, Bikowitz MJ, Lu J, Grassie D, Shultz ZP, Lopchuk JM, Chen J, Schonbrunn E. Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain. J Med Chem. 2022 Feb 22. doi: 10.1021/acs.jmedchem.1c01999. PMID:35191694 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01999

7l6x, resolution 2.75Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=7l6x&oldid=3913713"