1zz1: Difference between revisions
New page: left|200px<br /><applet load="1zz1" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zz1, resolution 1.57Å" /> '''Crystal structure of... |
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[[Image:1zz1.gif|left|200px]]<br /><applet load="1zz1" size=" | [[Image:1zz1.gif|left|200px]]<br /><applet load="1zz1" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1zz1, resolution 1.57Å" /> | caption="1zz1, resolution 1.57Å" /> | ||
'''Crystal structure of a HDAC-like protein with SAHA bound'''<br /> | '''Crystal structure of a HDAC-like protein with SAHA bound'''<br /> | ||
==Overview== | ==Overview== | ||
Histone deacetylases (HDACs) are among the most promising targets in | Histone deacetylases (HDACs) are among the most promising targets in cancer therapy. However, structural information greatly enhancing the design of HDAC inhibitors as novel chemotherapeutics has not been available on class 2 HDACs so far. Here we present the structure of the bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) that reveals high sequential and functional homology to human class 2 HDACs. FB188 HDAH is capable to remove the acetyl moiety from acetylated histones. Several HDAC-specific inhibitors, which have been shown to inhibit tumor activity in both pre-clinical models and in clinical trials, also inhibit FB188 HDAH. We have determined the crystal structure of FB188 HDAH at a resolution of 1.6 angstroms in complex with the reaction product acetate, as well as in complex with the inhibitors suberoylanilide hydroxamic acid (SAHA) and cyclopentyle-propionyle hydroxamic acid (CypX) at a resolution of 1.57 angstroms and 1.75 angstroms, respectively. FB188 HDAH exhibits the canonical fold of class 1 HDACs and contains a catalytic zinc ion. The highest structural diversity compared to class 1 enzymes is found in loop regions especially in the area around the entrance of the active site, indicating significant differences among the acetylated proteins binding to class 1 and 2 HDACs, respectively. | ||
==About this Structure== | ==About this Structure== | ||
1ZZ1 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bordetella_sp. Bordetella sp.] with ZN, K and SHH as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 1ZZ1 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bordetella_sp. Bordetella sp.] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=K:'>K</scene> and <scene name='pdbligand=SHH:'>SHH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZZ1 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Ficner, R.]] | [[Category: Ficner, R.]] | ||
[[Category: Hildmann, C.]] | [[Category: Hildmann, C.]] | ||
[[Category: Nielsen, T | [[Category: Nielsen, T K.]] | ||
[[Category: Schwienhorst, A.]] | [[Category: Schwienhorst, A.]] | ||
[[Category: K]] | [[Category: K]] | ||
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[[Category: hydrolase]] | [[Category: hydrolase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:20:28 2008'' | ||
Revision as of 17:20, 21 February 2008
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Crystal structure of a HDAC-like protein with SAHA bound
OverviewOverview
Histone deacetylases (HDACs) are among the most promising targets in cancer therapy. However, structural information greatly enhancing the design of HDAC inhibitors as novel chemotherapeutics has not been available on class 2 HDACs so far. Here we present the structure of the bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) that reveals high sequential and functional homology to human class 2 HDACs. FB188 HDAH is capable to remove the acetyl moiety from acetylated histones. Several HDAC-specific inhibitors, which have been shown to inhibit tumor activity in both pre-clinical models and in clinical trials, also inhibit FB188 HDAH. We have determined the crystal structure of FB188 HDAH at a resolution of 1.6 angstroms in complex with the reaction product acetate, as well as in complex with the inhibitors suberoylanilide hydroxamic acid (SAHA) and cyclopentyle-propionyle hydroxamic acid (CypX) at a resolution of 1.57 angstroms and 1.75 angstroms, respectively. FB188 HDAH exhibits the canonical fold of class 1 HDACs and contains a catalytic zinc ion. The highest structural diversity compared to class 1 enzymes is found in loop regions especially in the area around the entrance of the active site, indicating significant differences among the acetylated proteins binding to class 1 and 2 HDACs, respectively.
About this StructureAbout this Structure
1ZZ1 is a Single protein structure of sequence from Bordetella sp. with , and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of a bacterial class 2 histone deacetylase homologue., Nielsen TK, Hildmann C, Dickmanns A, Schwienhorst A, Ficner R, J Mol Biol. 2005 Nov 18;354(1):107-20. Epub 2005 Oct 7. PMID:16242151
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