6uo4: Difference between revisions
New page: '''Unreleased structure''' The entry 6uo4 is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 1 (CD1) Y363F mutant complexed with Trichostatin A== | ||
<StructureSection load='6uo4' size='340' side='right'caption='[[6uo4]], [[Resolution|resolution]] 1.27Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6uo4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UO4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UO4 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.2683098Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=TSN:TRICHOSTATIN+A'>TSN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6uo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uo4 OCA], [https://pdbe.org/6uo4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uo4 RCSB], [https://www.ebi.ac.uk/pdbsum/6uo4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uo4 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/F8W4B7_DANRE F8W4B7_DANRE] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Histone deacetylase 6 (HDAC6) is emerging as a target for inhibition in therapeutic strategies aimed at treating cancer, neurodegenerative disease, and other disorders. Among the metal-dependent HDAC isozymes, HDAC6 is unique in that it contains two catalytic domains, CD1 and CD2. CD2 is a tubulin deacetylase and a tau deacetylase, and the development of HDAC6-selective inhibitors has focused exclusively on this domain. In contrast, there is a dearth of structural and functional information regarding CD1, which exhibits much narrower substrate specificity in comparison with CD2. As the first step in addressing the CD1 information gap, we now present X-ray crystal structures of seven inhibitor complexes with wild-type, Y363F, and K330L HDAC6 CD1. These structures broaden our understanding of molecular features that are important for catalysis and inhibitor binding. The active site of HDAC6 CD1 is wider than that of CD2, which is unexpected in view of the narrow substrate specificity of CD1. Amino acid substitutions between HDAC6 CD1 and CD2, as well as conformational differences in conserved residues, define striking differences in active site contours. Catalytic activity measurements with HDAC6 CD1 confirm the preference for peptide substrates containing C-terminal acetyllysine residues. However, these measurements also show that CD1 exhibits weak activity for peptide substrates bearing certain small amino acids on the carboxyl side of the scissile acetyllysine residue. Taken together, these results establish a foundation for understanding the structural basis of HDAC6 CD1 catalysis and inhibition, pointing to possible avenues for the development of HDAC6 CD1-selective inhibitors. | |||
Structural Basis of Catalysis and Inhibition of HDAC6 CD1, the Enigmatic Catalytic Domain of Histone Deacetylase 6.,Osko JD, Christianson DW Biochemistry. 2019 Dec 2. doi: 10.1021/acs.biochem.9b00934. PMID:31755702<ref>PMID:31755702</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6uo4" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Danio rerio]] | |||
[[Category: Large Structures]] | |||
[[Category: Christianson DW]] | |||
[[Category: Osko JD]] | |||
Latest revision as of 10:55, 11 October 2023
Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 1 (CD1) Y363F mutant complexed with Trichostatin ACrystal structure of Danio rerio histone deacetylase 6 catalytic domain 1 (CD1) Y363F mutant complexed with Trichostatin A
Structural highlights
FunctionPublication Abstract from PubMedHistone deacetylase 6 (HDAC6) is emerging as a target for inhibition in therapeutic strategies aimed at treating cancer, neurodegenerative disease, and other disorders. Among the metal-dependent HDAC isozymes, HDAC6 is unique in that it contains two catalytic domains, CD1 and CD2. CD2 is a tubulin deacetylase and a tau deacetylase, and the development of HDAC6-selective inhibitors has focused exclusively on this domain. In contrast, there is a dearth of structural and functional information regarding CD1, which exhibits much narrower substrate specificity in comparison with CD2. As the first step in addressing the CD1 information gap, we now present X-ray crystal structures of seven inhibitor complexes with wild-type, Y363F, and K330L HDAC6 CD1. These structures broaden our understanding of molecular features that are important for catalysis and inhibitor binding. The active site of HDAC6 CD1 is wider than that of CD2, which is unexpected in view of the narrow substrate specificity of CD1. Amino acid substitutions between HDAC6 CD1 and CD2, as well as conformational differences in conserved residues, define striking differences in active site contours. Catalytic activity measurements with HDAC6 CD1 confirm the preference for peptide substrates containing C-terminal acetyllysine residues. However, these measurements also show that CD1 exhibits weak activity for peptide substrates bearing certain small amino acids on the carboxyl side of the scissile acetyllysine residue. Taken together, these results establish a foundation for understanding the structural basis of HDAC6 CD1 catalysis and inhibition, pointing to possible avenues for the development of HDAC6 CD1-selective inhibitors. Structural Basis of Catalysis and Inhibition of HDAC6 CD1, the Enigmatic Catalytic Domain of Histone Deacetylase 6.,Osko JD, Christianson DW Biochemistry. 2019 Dec 2. doi: 10.1021/acs.biochem.9b00934. PMID:31755702[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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