5b8d

Crystal structure of a low occupancy fragment candidate (N-(4-Methyl-1,3-thiazol-2-yl)propanamide) bound adjacent to the ubiquitin binding pocket of the HDAC6 zinc-finger domainCrystal structure of a low occupancy fragment candidate (N-(4-Methyl-1,3-thiazol-2-yl)propanamide) bound adjacent to the ubiquitin binding pocket of the HDAC6 zinc-finger domain

Structural highlights

5b8d is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.05Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HDAC6_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 (By similarity). Plays a central role in microtubule-dependent cell motility via deacetylation of tubulin.^[1] ^[2] In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome. Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy.^[3] ^[4]

Publication Abstract from PubMed

Inhibitors of HDAC6 have attractive potential in numerous cancers. HDAC6 inhibitors to date target the catalytic domains, but targeting the unique zinc-finger ubiquitin-binding domain (Zf-UBD) of HDAC6 may be an attractive alternative strategy. We developed X-ray crystallography and biophysical assays to identify and characterize small molecules capable of binding to the Zf-UBD and competing with ubiquitin binding. Our results revealed two adjacent ligand-able pockets of HDAC6 Zf-UBD and the first functional ligands for this domain.

Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin.,Harding RJ, Ferreira de Freitas R, Collins P, Franzoni I, Ravichandran M, Ouyang H, Juarez-Ornelas KA, Lautens M, Schapira M, von Delft F, Santhakumar V, Arrowsmith CH J Med Chem. 2017 Nov 9;60(21):9090-9096. doi: 10.1021/acs.jmedchem.7b00933. Epub , 2017 Oct 27. PMID:29019676^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. HDAC6 is a microtubule-associated deacetylase. Nature. 2002 May 23;417(6887):455-8. PMID:12024216 doi:http://dx.doi.org/10.1038/417455a
↑ Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol. 2007 Sep 10;178(6):1025-38. PMID:17846173 doi:10.1083/jcb.200611128
↑ Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. HDAC6 is a microtubule-associated deacetylase. Nature. 2002 May 23;417(6887):455-8. PMID:12024216 doi:http://dx.doi.org/10.1038/417455a
↑ Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol. 2007 Sep 10;178(6):1025-38. PMID:17846173 doi:10.1083/jcb.200611128
↑ Harding RJ, Ferreira de Freitas R, Collins P, Franzoni I, Ravichandran M, Ouyang H, Juarez-Ornelas KA, Lautens M, Schapira M, von Delft F, Santhakumar V, Arrowsmith CH. Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin. J Med Chem. 2017 Nov 9;60(21):9090-9096. doi: 10.1021/acs.jmedchem.7b00933. Epub , 2017 Oct 27. PMID:29019676 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00933

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OCA

[1] Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. HDAC6 is a microtubule-associated deacetylase. Nature. 2002 May 23;417(6887):455-8. PMID:12024216 doi:http://dx.doi.org/10.1038/417455a

[2] Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol. 2007 Sep 10;178(6):1025-38. PMID:17846173 doi:10.1083/jcb.200611128

[3] Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. HDAC6 is a microtubule-associated deacetylase. Nature. 2002 May 23;417(6887):455-8. PMID:12024216 doi:http://dx.doi.org/10.1038/417455a

[4] Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol. 2007 Sep 10;178(6):1025-38. PMID:17846173 doi:10.1083/jcb.200611128

[5] Harding RJ, Ferreira de Freitas R, Collins P, Franzoni I, Ravichandran M, Ouyang H, Juarez-Ornelas KA, Lautens M, Schapira M, von Delft F, Santhakumar V, Arrowsmith CH. Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin. J Med Chem. 2017 Nov 9;60(21):9090-9096. doi: 10.1021/acs.jmedchem.7b00933. Epub , 2017 Oct 27. PMID:29019676 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00933

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