6pd8: Difference between revisions
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==Crystal structure of MYST acetyltransferase domain in complex with inhibitor 39== | |||
<StructureSection load='6pd8' size='340' side='right'caption='[[6pd8]], [[Resolution|resolution]] 2.74Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6pd8]] 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=6PD8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PD8 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]] 2.738Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=O9D:5-ethoxy-2-fluoro-3-methyl-N-(phenylsulfonyl)benzohydrazide'>O9D</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=6pd8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pd8 OCA], [https://pdbe.org/6pd8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pd8 RCSB], [https://www.ebi.ac.uk/pdbsum/6pd8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pd8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/KAT8_HUMAN KAT8_HUMAN] Histone acetyltransferase which may be involved in transcriptional activation. May influence the function of ATM. As part of the MSL complex it is involved in acetylation of nucleosomal histone H4 producing specifically H4K16ac. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. That activity is less specific than the one of the MSL complex.<ref>PMID:12397079</ref> <ref>PMID:15923642</ref> <ref>PMID:20018852</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 muM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 muM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats. | |||
Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents.,Priebbenow DL, Leaver DJ, Nguyen N, Cleary B, Lagiakos HR, Sanchez J, Xue L, Huang F, Sun Y, Mujumdar P, Mudududdla R, Varghese S, Teguh S, Charman SA, White KL, Shackleford DM, Katneni K, Cuellar M, Strasser JM, Dahlin JL, Walters MA, Street IP, Monahan BJ, Jarman KE, Jousset Sabroux H, Falk H, Chung MC, Hermans SJ, Downer NL, Parker MW, Voss AK, Thomas T, Baell JB J Med Chem. 2020 Mar 19. doi: 10.1021/acs.jmedchem.9b02071. PMID:32118427<ref>PMID:32118427</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6pd8" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Histone acetyltransferase 3D structures|Histone acetyltransferase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Baell JB]] | |||
[[Category: Hermans SJ]] | |||
[[Category: Parker MW]] | |||
[[Category: Thomas T]] | |||
Latest revision as of 10:27, 11 October 2023
Crystal structure of MYST acetyltransferase domain in complex with inhibitor 39Crystal structure of MYST acetyltransferase domain in complex with inhibitor 39
Structural highlights
FunctionKAT8_HUMAN Histone acetyltransferase which may be involved in transcriptional activation. May influence the function of ATM. As part of the MSL complex it is involved in acetylation of nucleosomal histone H4 producing specifically H4K16ac. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. That activity is less specific than the one of the MSL complex.[1] [2] [3] Publication Abstract from PubMedA high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 muM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 muM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats. Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents.,Priebbenow DL, Leaver DJ, Nguyen N, Cleary B, Lagiakos HR, Sanchez J, Xue L, Huang F, Sun Y, Mujumdar P, Mudududdla R, Varghese S, Teguh S, Charman SA, White KL, Shackleford DM, Katneni K, Cuellar M, Strasser JM, Dahlin JL, Walters MA, Street IP, Monahan BJ, Jarman KE, Jousset Sabroux H, Falk H, Chung MC, Hermans SJ, Downer NL, Parker MW, Voss AK, Thomas T, Baell JB J Med Chem. 2020 Mar 19. doi: 10.1021/acs.jmedchem.9b02071. PMID:32118427[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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