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5fcw

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Revision as of 06:46, 19 July 2023

HDAC8 Complexed with a Hydroxamic Acid

Structural highlights

5fcw is a 2 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 1.979Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HDAC8_HUMAN Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. May play a role in smooth muscle cell contractility.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Histone deacetylases (HDACs) catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins, and play a critical role in the regulation of many biological processes, including cell differentiation, proliferation, senescence, and apoptosis. Aberrant HDAC activity is associated with cancer, making these enzymes important targets for drug design. In general, HDAC inhibitors (HDACi) block the proliferation of tumor cells by inducing cell differentiation, cell cycle arrest, and/or apoptosis, and comprise some of the leading therapies in cancer treatments. To date, four HDACi have been FDA approved for the treatment of cancers: suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza(R)), romidepsin (FK228, Istodax(R)), belinostat (Beleodaq(R)), and panobinostat (Farydak(R)). Most current inhibitors are pan-HDACi, and non-selectively target a number of HDAC isoforms. Six previously reported HDACi were rationally designed, however, to target a unique sub-pocket found only in HDAC8. While these inhibitors were indeed potent against HDAC8, and even demonstrated specificity for HDAC8 over HDACs 1 and 6, there were no structural data to confirm the mode of binding. Here we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98A resolution. We also describe the use of molecular docking studies to explore the binding interactions of the other 5 related HDACi. Our studies confirm that the HDACi induce the formation of and bind in the HDAC8-specific subpocket, offering insights into isoform-specific inhibition.

Structure of 'linkerless' hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket.,Tabackman AA, Frankson R, Marsan ES, Perry K, Cole KE J Struct Biol. 2016 Sep;195(3):373-8. doi: 10.1016/j.jsb.2016.06.023. Epub 2016, Jun 29. PMID:27374062^[5]

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

References

↑ Hu E, Chen Z, Fredrickson T, Zhu Y, Kirkpatrick R, Zhang GF, Johanson K, Sung CM, Liu R, Winkler J. Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor. J Biol Chem. 2000 May 19;275(20):15254-64. PMID:10748112 doi:http://dx.doi.org/10.1074/jbc.M908988199
↑ Buggy JJ, Sideris ML, Mak P, Lorimer DD, McIntosh B, Clark JM. Cloning and characterization of a novel human histone deacetylase, HDAC8. Biochem J. 2000 Aug 15;350 Pt 1:199-205. PMID:10926844
↑ Van den Wyngaert I, de Vries W, Kremer A, Neefs J, Verhasselt P, Luyten WH, Kass SU. Cloning and characterization of human histone deacetylase 8. FEBS Lett. 2000 Jul 28;478(1-2):77-83. PMID:10922473
↑ Lee H, Rezai-Zadeh N, Seto E. Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. Mol Cell Biol. 2004 Jan;24(2):765-73. PMID:14701748
↑ Tabackman AA, Frankson R, Marsan ES, Perry K, Cole KE. Structure of 'linkerless' hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket. J Struct Biol. 2016 Sep;195(3):373-8. doi: 10.1016/j.jsb.2016.06.023. Epub 2016, Jun 29. PMID:27374062 doi:http://dx.doi.org/10.1016/j.jsb.2016.06.023

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5fcw"

Categories: Homo sapiens | Large Structures | Cole KE | Perry K

@@ Line 3: / Line 3: @@
 <StructureSection load='5fcw' size='340' side='right'caption='[[5fcw]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5fcw]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FCW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5FCW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5fcw]] is a 2 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=5FCW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FCW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5YA:4-NAPHTHALEN-1-YL-~{N}-OXIDANYL-BENZAMIDE'>5YA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.979&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HDAC8, HDACL1, CDA07 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5YA:4-NAPHTHALEN-1-YL-~{N}-OXIDANYL-BENZAMIDE'>5YA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_deacetylase Histone deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.98 3.5.1.98] </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=5fcw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fcw OCA], [https://pdbe.org/5fcw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fcw RCSB], [https://www.ebi.ac.uk/pdbsum/5fcw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fcw ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5fcw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fcw OCA], [http://pdbe.org/5fcw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fcw RCSB], [http://www.ebi.ac.uk/pdbsum/5fcw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fcw ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/HDAC8_HUMAN HDAC8_HUMAN]] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. May play a role in smooth muscle cell contractility.<ref>PMID:10748112</ref> <ref>PMID:10926844</ref> <ref>PMID:10922473</ref> <ref>PMID:14701748</ref>
+[https://www.uniprot.org/uniprot/HDAC8_HUMAN HDAC8_HUMAN] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. May play a role in smooth muscle cell contractility.<ref>PMID:10748112</ref> <ref>PMID:10926844</ref> <ref>PMID:10922473</ref> <ref>PMID:14701748</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Histone deacetylase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Cole, K E]]
+[[Category: Cole KE]]
-[[Category: Perry, K]]
+[[Category: Perry K]]
-[[Category: Hdac8]]
-[[Category: Hydrolase]]
-[[Category: Hydroxamic acid]]

5fcw

From Proteopedia

Revision as of 06:46, 19 July 2023

HDAC8 Complexed with a Hydroxamic Acid

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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