PDBsum entry: 1c3p

Lyase

PDB id: 1c3p

Contents

Protein chain

372 a.a. *

Waters ×228

* Residue conservation analysis

PDB id:

1c3p

Name:

Lyase

Title:

Crystal structure of an hdac homolog from aquifex aeolicus

Structure:

Protein (hdlp (histone deacetylase-like protein) ). Chain: a. Engineered: yes

Source:

Aquifex aeolicus. Organism_taxid: 63363. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.80Å R-factor: 0.198 R-free: 0.240

Authors:

M.S.Finnin,J.R.Donigian,N.P.Pavletich

Key ref:

M.S.Finnin et al. (1999). Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature, 401, 188-193. PubMed id: 10490031 DOI: 10.1038/43710

Date:

28-Jul-99 Release date: 15-Sep-99

Protein chain

O67135  (O67135_AQUAE) -  Acetoin utilization protein

Seq: 375 a.a.

Struc: 372 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1038/43710

Nature 401:188-193 (1999)

PubMed id: 10490031

Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors.

M.S.Finnin, J.R.Donigian, A.Cohen, V.M.Richon, R.A.Rifkind, P.A.Marks, R.Breslow, N.P.Pavletich.

ABSTRACT

Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression. HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers. HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects, as they can inhibit cell growth, induce terminal differentiation and prevent the formation of tumours in mice models, and they are effective in the treatment of promyelocytic leukemia. Here we describe the structure of the histone deacetylase catalytic core, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolicus, that shares 35.2% identity with human HDAC1 over 375 residues, deacetylates histones in vitro and is inhibited by TSA and SAHA. The deacetylase, deacetylase-TSA and deacetylase-SAHA structures reveal an active site consisting of a tubular pocket, a zinc-binding site and two Asp-His charge-relay systems, and establish the mechanism of HDAC inhibition. The residues that make up the active site and contact the inhibitors are conserved across the HDAC family. These structures also suggest a mechanism for the deacetylation reaction and provide a framework for the further development of HDAC inhibitors as antitumour agents.

Selected figure(s)

Figure 3.
Figure 3 TSA binds inside the pocket making contacts to residues at the rim, walls and bottom of the pocket. a, Space-filling representation of TSA in the active-site pocket. The hydroxamic acid group, most of the aliphatic chain and part of the dimethylamino-phenyl group of TSA are buried (60% of TSA's surface area). The internal cavity has a volume of 144 ?3. b, Closeup stereo view of the structure of the HDLP-Zn2+-TSA complex in an orientation similar to Fig. 2a except for a 90° rotation about the vertical axis. TSA is in white; active-site residues and residues that contact TSA, which are all identical in HDAC1 except Tyr 91, are in yellow. c, Schematic representation of HDLP-TSA interactions. TSA is in black and the protein is in red. HDLP residues are labelled in red with their counterparts in HDAC1 indicated in black. Thatched semi-circles indicate van der Waals contacts between hydrophobic protein residues and TSA. Hydrogen bonds are shown as green dashed lines. d, Surface representation of the HDLP-TSA interface in a similar orientation to b. The protein surface is coloured according to residue identity with HDAC1. Cyan indicates residues that are identical in HDAC1.

Figure 4.
Figure 4 SAHA binds HDLP like TSA, but its aliphatic chain and cap groups make fewer contacts. Close-up view of the HDLP-Zn2+-SAHA complex in the same orientation and colour scheme as Fig. 3b. Note that Tyr 91 is not in the TSA-bound conformation.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1999, 401, 188-193) copyright 1999.

Figures were selected by an automated process.