7l6x: Difference between revisions
No edit summary |
No edit summary |
||
| Line 3: | Line 3: | ||
<StructureSection load='7l6x' size='340' side='right'caption='[[7l6x]], [[Resolution|resolution]] 2.75Å' scene=''> | <StructureSection load='7l6x' size='340' side='right'caption='[[7l6x]], [[Resolution|resolution]] 2.75Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7l6x]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[7l6x]] 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=7L6X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L6X FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=G9V:6-(but-3-en-1-yl)-4-[1-methyl-6-(morpholine-4-carbonyl)-1H-benzimidazol-4-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one'>G9V</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.75Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=G9V:6-(but-3-en-1-yl)-4-[1-methyl-6-(morpholine-4-carbonyl)-1H-benzimidazol-4-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one'>G9V</scene></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=7l6x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l6x OCA], [https://pdbe.org/7l6x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l6x RCSB], [https://www.ebi.ac.uk/pdbsum/7l6x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l6x ProSAT]</span></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=7l6x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l6x OCA], [https://pdbe.org/7l6x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l6x RCSB], [https://www.ebi.ac.uk/pdbsum/7l6x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l6x ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
[https://www.uniprot.org/uniprot/TAF1_HUMAN TAF1_HUMAN] Defects in TAF1 are the cause of dystonia type 3 (DYT3) [MIM:[https://omim.org/entry/314250 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.<ref>PMID:12928496</ref> <ref>PMID:17273961</ref> | |||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/TAF1_HUMAN 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.<ref>PMID:2038334</ref> <ref>PMID:8450888</ref> <ref>PMID:8625415</ref> <ref>PMID:9660973</ref> <ref>PMID:9858607</ref> <ref>PMID:11278496</ref> <ref>PMID:15053879</ref> | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 21: | Line 21: | ||
</div> | </div> | ||
<div class="pdbe-citations 7l6x" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7l6x" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Transcription initiation factors 3D structures|Transcription initiation factors 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Karim | [[Category: Karim MR]] | ||
[[Category: Schonbrunn | [[Category: Schonbrunn E]] | ||
Latest revision as of 18:39, 18 October 2023
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
DiseaseTAF1_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] FunctionTAF1_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 PubMedBromodomains 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 AlsoReferences
|
| ||||||||||||||||||