View source for 7p4s


==BROMODOMAIN OF HUMAN TAF1 (2) WITH naphthyridinone compound==
<StructureSection load='7p4s' size='340' side='right'caption='[[7p4s]], [[Resolution|resolution]] 2.17&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7p4s]] 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=7P4S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P4S FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.17&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5LV:8-[[1-(3-azanylpropyl)piperidin-4-yl]amino]-5-[5-(hydroxymethyl)pyridin-3-yl]-3-methyl-1~{H}-1,7-naphthyridin-2-one'>5LV</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=7p4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p4s OCA], [https://pdbe.org/7p4s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p4s RCSB], [https://www.ebi.ac.uk/pdbsum/7p4s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p4s ProSAT]</span></td></tr>
</table>
== 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 ==
[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;">
== Publication Abstract from PubMed ==
Bromodomain containing proteins and the acetyl-lysine binding bromodomains contained therein are increasingly attractive targets for the development of novel epigenetic therapeutics. To help validate this target class and unravel the complex associated biology, there has been a concerted effort to develop selective small molecule bromodomain inhibitors. Herein we describe the structure-based efforts and multiple challenges encountered in optimizing a naphthyridone template into selective TAF1(2) bromodomain inhibitors which, while unsuitable as chemical probes themselves, show promise for the future development of small molecules to interrogate TAF1(2) biology. Key to this work was the introduction and modulation of the basicity of a pendant amine which had a substantial impact on not only bromodomain selectivity but also cellular target engagement.

Optimization of Naphthyridones into Selective TATA-Binding Protein Associated Factor 1 (TAF1) Bromodomain Inhibitors.,Clegg MA, Theodoulou NH, Bamborough P, Chung CW, Craggs PD, Demont EH, Gordon LJ, Liwicki GM, Phillipou A, Tomkinson NCO, Prinjha RK, Humphreys PG ACS Med Chem Lett. 2021 Aug 3;12(8):1308-1317. doi:, 10.1021/acsmedchemlett.1c00294. eCollection 2021 Aug 12. PMID:34413961<ref>PMID:34413961</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7p4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Transcription initiation factors 3D structures|Transcription initiation factors 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chung C]]