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5dc5

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Revision as of 11:20, 25 December 2019

Crystal structure of D176N HDAC8 in complex with M344

Structural highlights

5dc5 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5dc6, 5dc7, 5dc8
Gene:	HDAC8, HDACL1, CDA07 (HUMAN)
Activity:	Histone deacetylase, with EC number 3.5.1.98
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) regulate cellular processes such as differentiation and apoptosis and are targeted by anticancer therapeutics in development and in the clinic. HDAC8 is a metal-dependent class I HDAC and is proposed to use a general acid-base catalytic pair in the mechanism of amide bond hydrolysis. Here, we report site-directed mutagenesis and enzymological measurements to elucidate the catalytic mechanism of HDAC8. Specifically, we focus on the catalytic function of Y306 and the histidine-aspartate dyads H142-D176 and H143-D183. Additionally, we report X-ray crystal structures of four representative HDAC8 mutants: D176N, D176N/Y306F, D176A/Y306F, and H142A/Y306F. These structures provide a useful framework for understanding enzymological measurements. The pH dependence of kcat/KM for wild-type Co(II)-HDAC8 is bell-shaped with two pKa values of 7.4 and 10.0. The upper pKa reflects the ionization of the metal-bound water molecule and shifts to 9.1 in Zn(II)-HDAC8. The H142A mutant has activity 230-fold lower than that of wild-type HDAC8, but the pKa1 value is not altered. Y306F HDAC8 is 150-fold less active than the wild-type enzyme; crystal structures show that Y306 hydrogen bonds with the zinc-bound substrate carbonyl, poised for transition state stabilization. The H143A and H142A/H143A mutants exhibit activity that is >80000-fold lower than that of wild-type HDAC8; the buried D176N and D176A mutants have significant catalytic effects, with more subtle effects caused by D183N and D183A. These enzymological and structural studies strongly suggest that H143 functions as a single general base-general acid catalyst, while H142 remains positively charged and serves as an electrostatic catalyst for transition state stabilization.

General Base-General Acid Catalysis in Human Histone Deacetylase 8.,Gantt SM Fsgm, Decroos C, Lee MS, Gullett LE, Bowman CM, Christianson DW, Fierke CA Biochemistry. 2016 Jan 25. PMID:26806311^[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
↑ Gantt SM Fsgm, Decroos C, Lee MS, Gullett LE, Bowman CM, Christianson DW, Fierke CA. General Base-General Acid Catalysis in Human Histone Deacetylase 8. Biochemistry. 2016 Jan 25. PMID:26806311 doi:http://dx.doi.org/10.1021/acs.biochem.5b01327

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/5dc5"

@@ Line 1: / Line 1: @@
 ==Crystal structure of D176N HDAC8 in complex with M344==
-<StructureSection load='5dc5' size='340' side='right' caption='[[5dc5]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
+<StructureSection load='5dc5' size='340' side='right'caption='[[5dc5]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5dc5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DC5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DC5 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5dc5]] 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=5DC5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DC5 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B3N:4-(DIMETHYLAMINO)-N-[7-(HYDROXYAMINO)-7-OXOHEPTYL]BENZAMIDE'>B3N</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5dc6|5dc6]], [[5dc7|5dc7]], [[5dc8|5dc8]]</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='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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5dc5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dc5 OCA], [http://pdbe.org/5dc5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dc5 RCSB], [http://www.ebi.ac.uk/pdbsum/5dc5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dc5 ProSAT]</span></td></tr>
@@ Line 22: / Line 23: @@
 ==See Also==
-*[[Histone deacetylase|Histone deacetylase]]
+*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
 == References ==
 <references/>
@@ Line 28: / Line 29: @@
 </StructureSection>
 [[Category: Histone deacetylase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Christianson, D W]]
 [[Category: Decroos, C]]

5dc5

From Proteopedia

Revision as of 11:20, 25 December 2019

Crystal structure of D176N HDAC8 in complex with M344

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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