PDBsum entry 6htt

Hydrolase

PDB id: 6htt

Contents

Protein chains

397 a.a.

Ligands

GQZ ×4

DMF ×27

GOL ×20

Metals

_ZN ×4

__K ×8

Waters ×1365

PDB id:

6htt

Name:

Hydrolase

Title:

Crystal structure of schistosoma mansoni hdac8 complexed with a benzohydroxamate inhibitor 7

Structure:

Histone deacetylase. Chain: a, b, c, d. Engineered: yes

Source:

Schistosoma mansoni. Blood fluke. Organism_taxid: 6183. Gene: hdac8. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.75Å R-factor: 0.151 R-free: 0.183

Authors:

T.B.Shaik,M.Marek,C.Romier

Key ref:

M.Marek et al. (2018). Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants. J Med Chem, 61, 10000-10016. PubMed id: 30347148 DOI: 10.1021/acs.jmedchem.8b01087

Date:

04-Oct-18 Release date: 31-Oct-18

Protein chains

A5H660  (A5H660_SCHMA) -  histone deacetylase from Schistosoma mansoni

Seq: 440 a.a.

Struc: 397 a.a.

Enzyme reactions

• Enzyme class: E.C.3.5.1.98 - histone deacetylase.
• Reaction: N₆-acetyl-L-lysyl-[histone] + H2O = L-lysyl-[histone] + acetate

N(6)-acetyl-L-lysyl-[histone] + H2O = L-lysyl-[histone] (Bound ligand (Het Group name = GOL) matches with 42.86% similarity) + acetate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

DOI no: 10.1021/acs.jmedchem.8b01087

J Med Chem 61:10000-10016 (2018)

PubMed id: 30347148

Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.

M.Marek, T.B.Shaik, T.Heimburg, A.Chakrabarti, J.Lancelot, E.Ramos-Morales, C.Da Veiga, D.Kalinin, J.Melesina, D.Robaa, K.Schmidtkunz, T.Suzuki, R.Holl, E.Ennifar, R.J.Pierce, M.Jung, W.Sippl, C.Romier.

ABSTRACT

Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.