1c3p
From Proteopedia
(New page: 200px<br /><applet load="1c3p" size="450" color="white" frame="true" align="right" spinBox="true" caption="1c3p, resolution 1.80Å" /> '''CRYSTAL STRUCTURE OF...) |
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| - | [[Image:1c3p.gif|left|200px]]<br /><applet load="1c3p" size=" | + | [[Image:1c3p.gif|left|200px]]<br /><applet load="1c3p" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1c3p, resolution 1.80Å" /> | caption="1c3p, resolution 1.80Å" /> | ||
'''CRYSTAL STRUCTURE OF AN HDAC HOMOLOG FROM AQUIFEX AEOLICUS'''<br /> | '''CRYSTAL STRUCTURE OF AN HDAC HOMOLOG FROM AQUIFEX AEOLICUS'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Histone deacetylases (HDACs) mediate changes in nucleosome conformation | + | Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression. HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers. HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects, as they can inhibit cell growth, induce terminal differentiation and prevent the formation of tumours in mice models, and they are effective in the treatment of promyelocytic leukemia. Here we describe the structure of the histone deacetylase catalytic core, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolicus, that shares 35.2% identity with human HDAC1 over 375 residues, deacetylates histones in vitro and is inhibited by TSA and SAHA. The deacetylase, deacetylase-TSA and deacetylase-SAHA structures reveal an active site consisting of a tubular pocket, a zinc-binding site and two Asp-His charge-relay systems, and establish the mechanism of HDAC inhibition. The residues that make up the active site and contact the inhibitors are conserved across the HDAC family. These structures also suggest a mechanism for the deacetylation reaction and provide a framework for the further development of HDAC inhibitors as antitumour agents. |
==About this Structure== | ==About this Structure== | ||
| - | 1C3P is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Aquifex_aeolicus Aquifex aeolicus]. Full crystallographic information is available from [http:// | + | 1C3P is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Aquifex_aeolicus Aquifex aeolicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1C3P OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Aquifex aeolicus]] | [[Category: Aquifex aeolicus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Donigian, J | + | [[Category: Donigian, J R.]] |
| - | [[Category: Finnin, M | + | [[Category: Finnin, M S.]] |
| - | [[Category: Pavletich, N | + | [[Category: Pavletich, N P.]] |
[[Category: alpha/beta fold]] | [[Category: alpha/beta fold]] | ||
[[Category: lyase]] | [[Category: lyase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:02:03 2008'' |
Revision as of 10:02, 21 February 2008
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CRYSTAL STRUCTURE OF AN HDAC HOMOLOG FROM AQUIFEX AEOLICUS
Overview
Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression. HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers. HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects, as they can inhibit cell growth, induce terminal differentiation and prevent the formation of tumours in mice models, and they are effective in the treatment of promyelocytic leukemia. Here we describe the structure of the histone deacetylase catalytic core, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolicus, that shares 35.2% identity with human HDAC1 over 375 residues, deacetylates histones in vitro and is inhibited by TSA and SAHA. The deacetylase, deacetylase-TSA and deacetylase-SAHA structures reveal an active site consisting of a tubular pocket, a zinc-binding site and two Asp-His charge-relay systems, and establish the mechanism of HDAC inhibition. The residues that make up the active site and contact the inhibitors are conserved across the HDAC family. These structures also suggest a mechanism for the deacetylation reaction and provide a framework for the further development of HDAC inhibitors as antitumour agents.
About this Structure
1C3P is a Single protein structure of sequence from Aquifex aeolicus. Full crystallographic information is available from OCA.
Reference
Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors., Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP, Nature. 1999 Sep 9;401(6749):188-93. PMID:10490031
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