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5bwz

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Revision as of 06:11, 7 June 2023

Crystal structure of S39E HDAC8 in complex with Droxinostat

Structural highlights

5bwz 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.
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 deacetylase (HDAC) enzymes that catalyze removal of acetyl-lysine post-translational modifications are frequently post-translationally modified. HDAC8 is phosphorylated within the deacetylase domain at conserved residue serine 39, which leads to decreased catalytic activity. HDAC8 phosphorylation at S39 is unique in its location and function and may represent a novel mode of deacetylation regulation. To better understand the impact of phosphorylation of HDAC8 on enzyme structure and function, we performed crystallographic, kinetic, and molecular dynamics studies of the S39E HDAC8 phosphomimetic mutant. This mutation decreases the level of deacetylation of peptides derived from acetylated nuclear and cytoplasmic proteins. However, the magnitude of the effect depends on the peptide sequence and the identity of the active site metal ion [Zn(II) vs Fe(II)], with the value of kcat/KM for the mutant decreasing 9- to >200-fold compared to that of wild-type HDAC8. Furthermore, the dissociation rate constant of the active site metal ion increases by approximately 10-fold. S39E HDAC8 was crystallized in complex with the inhibitor Droxinostat, revealing that phosphorylation of S39, as mimicked by the glutamate side chain, perturbs local structure through distortion of the L1 loop. Molecular dynamics simulations of both S39E and phosphorylated S39 HDAC8 demonstrate that the perturbation of the L1 loop likely occurs because of the lost hydrogen bond between D29 and S39. Furthermore, the S39 perturbation causes structural changes that propagate through the protein scaffolding to influence function in the active site. These data demonstrate that phosphorylation plays an important regulatory role for HDAC8 by affecting ligand binding, catalytic efficiency, and substrate selectivity.

Phosphorylation of Histone Deacetylase 8: Structural and Mechanistic Analysis of the Phosphomimetic S39E Mutant.,Welker Leng KR, Castaneda CA, Decroos C, Islam B, Haider SM, Christianson DW, Fierke CA Biochemistry. 2019 Nov 12;58(45):4480-4493. doi: 10.1021/acs.biochem.9b00653., Epub 2019 Nov 4. PMID:31633931^[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
↑ Welker Leng KR, Castaneda CA, Decroos C, Islam B, Haider SM, Christianson DW, Fierke CA. Phosphorylation of Histone Deacetylase 8: Structural and Mechanistic Analysis of the Phosphomimetic S39E Mutant. Biochemistry. 2019 Nov 12;58(45):4480-4493. doi: 10.1021/acs.biochem.9b00653., Epub 2019 Nov 4. PMID:31633931 doi:http://dx.doi.org/10.1021/acs.biochem.9b00653

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/5bwz"

Categories: Homo sapiens | Large Structures | Christianson DW | Decroos C

@@ Line 3: / Line 3: @@
 <StructureSection load='5bwz' size='340' side='right'caption='[[5bwz]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5bwz]] 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=5BWZ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5BWZ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5bwz]] 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=5BWZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BWZ FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=XCH:DROXINOSTAT'>XCH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5bwz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bwz OCA], [https://pdbe.org/5bwz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bwz RCSB], [https://www.ebi.ac.uk/pdbsum/5bwz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bwz ProSAT]</span></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'>[http://proteopedia.org/fgij/fg.htm?mol=5bwz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bwz OCA], [http://pdbe.org/5bwz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bwz RCSB], [http://www.ebi.ac.uk/pdbsum/5bwz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5bwz 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 25: @@
 __TOC__
 </StructureSection>
-[[Category: Histone deacetylase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Christianson, D W]]
+[[Category: Christianson DW]]
-[[Category: Decroos, C]]
+[[Category: Decroos C]]
-[[Category: Arginase/deacetylase fold]]
-[[Category: Enzyme inhibitor-complex]]
-[[Category: Hydrolase]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]

5bwz

From Proteopedia

Revision as of 06:11, 7 June 2023

Crystal structure of S39E HDAC8 in complex with Droxinostat

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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