| Structural highlights
6cea is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Gene: | HDAC6, KIAA0901, JM21 (HUMAN) |
| Activity: | Histone deacetylase, with EC number 3.5.1.98 |
| 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
HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155, are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.
Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors.,Ferreira de Freitas R, Harding RJ, Franzoni I, Ravichandran M, Mann MK, Ouyang H, Lautens M, Santhakumar V, Arrowsmith CH, Schapira M J Med Chem. 2018 May 9. doi: 10.1021/acs.jmedchem.8b00258. PMID:29741882[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Ferreira de Freitas R, Harding RJ, Franzoni I, Ravichandran M, Mann MK, Ouyang H, Lautens M, Santhakumar V, Arrowsmith CH, Schapira M. Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors. J Med Chem. 2018 May 9. doi: 10.1021/acs.jmedchem.8b00258. PMID:29741882 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00258
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