PDBsum entry 2v1d

Oxidoreductase/repressor

PDB id: 2v1d

Contents

Protein chains

666 a.a. *

133 a.a. *

16 a.a. *

Ligands

FAD

* Residue conservation analysis

PDB id:

2v1d

Name:

Oxidoreductase/repressor

Title:

Structural basis of lsd1-corest selectivity in histone h3 recognition

Structure:

Lysine-specific histone demethylase 1. Chain: a. Fragment: residues 123-852. Synonym: flavin-containing amine oxidase domain-containing protein 2, braf35-hdac complex protein bhc110. Engineered: yes. Rest corepressor 1. Chain: b. Fragment: 305-482.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

3.10Å R-factor: 0.224 R-free: 0.239

Authors:

F.Forneris,C.Binda,A.Adamo,E.Battaglioli,A.Mattevi

Key ref:

F.Forneris et al. (2007). Structural basis of LSD1-CoREST selectivity in histone H3 recognition. J Biol Chem, 282, 20070-20074. PubMed id: 17537733 DOI: 10.1074/jbc.C700100200

Date:

23-May-07 Release date: 29-May-07

Protein chain

O60341  (KDM1A_HUMAN) -  Lysine-specific histone demethylase 1A from Homo sapiens

Seq: 852 a.a.

Struc: 666 a.a.

Protein chain

Q9UKL0  (RCOR1_HUMAN) -  REST corepressor 1 from Homo sapiens

Seq: 485 a.a.

Struc: 133 a.a.

Protein chain

Q16695  (H31T_HUMAN) -  Histone H3.1t from Homo sapiens

Seq: 136 a.a.

Struc: 16 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chain A: E.C.1.14.99.66 - [histone-H3]-N(6),N(6)-dimethyl-L-lysine(4) FAD-dependent demethylase.
• Reaction: N₆,N₆-dimethyl-L-lysyl₄-[histone H3] + 2 A + 2 H2O = L-lysyl₄- [histone H3] + 2 formaldehyde + 2 AH2

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

Key reference

DOI no: 10.1074/jbc.C700100200

J Biol Chem 282:20070-20074 (2007)

PubMed id: 17537733

Structural basis of LSD1-CoREST selectivity in histone H3 recognition.

F.Forneris, C.Binda, A.Adamo, E.Battaglioli, A.Mattevi.

ABSTRACT

Histone demethylase LSD1 regulates transcription by demethylating Lys(4) of histone H3. The crystal structure of the enzyme in complex with CoREST and a substrate-like peptide inhibitor highlights an intricate network of interactions and a folded conformation of the bound peptide. The core of the peptide structure is formed by Arg(2), Gln(5), and Ser(10), which are engaged in specific intramolecular H-bonds. Several charged side chains on the surface of the substrate-binding pocket establish electrostatic interactions with the peptide. The three-dimensional structure predicts that methylated Lys(4) binds in a solvent inaccessible position in front of the flavin cofactor. This geometry is fully consistent with the demethylation reaction being catalyzed through a flavin-mediated oxidation of the substrate amino-methyl group. These features dictate the exquisite substrate specificity of LSD1 and provide a structural framework to explain the fine tuning of its catalytic activity and the active role of CoREST in substrate recognition.

Selected figure(s)

Figure 1.
FIGURE 1. Crystal structure of LSD1-CoREST in complex with pLys4Met H3 peptide. A, ribbon diagram of the structure. LSD1 is in blue, CoREST in red, and the peptide in green. The FAD cofactor is shown as a yellow ball-and-stick. The final model consists of residues 171–836 of LSD1, residues 308–440 of CoREST, and residues 1–16 of pLys4Met peptide. B, fitting of the refined pLys4Met peptide in the unbiased electron density calculated with weighted 2F[o] – F[c] coefficients. The map was calculated prior inclusion of the peptide atoms in the refinement calculations. The contour level is 1.2 , and the resolution is 3.1 Å. The sequence of the histone H3 peptide used for the x-ray analysis is ^1ARTMQTARKSTGGKAPRKQLA^21.

Figure 2.
FIGURE 2. Recognition of H3 peptide by LSD1. A, surface view of the peptide-binding pocket. The peptide is shown in green and the LSD1 surface in gray. Nitrogens are blue, oxygens red, sulfurs yellow, and carbons green. The positions of negatively charged residues lining the peptide-binding site are labeled. The C trace of CoREST residues 308–314 is shown in red, highlighting their proximity to the LSD1 372–395 -helix that is integral part of the peptide-binding site. The orientation is the same as in Fig. 1A. B, three-dimensional view of the peptide-binding mode. Nitrogens are blue, oxygens red, and sulfurs yellow. Carbons of peptide and protein residues are in green and gray, respectively. The flavin cofactor is yellow. With respect to Fig. 1A, the structure is rotated by 180° about the vertical axis in the plane of the drawing. C, schematic representation of the peptide-protein interactions. D, model of dimethyl Lys^4 peptide substrate bound in the active site. Orientation and atom colors are the same as described in B. The modeling was carried out assuming that the C -C -C atoms of dimethyl Lys^4 adopt the same conformation of the C -C -S atoms of pMet^4 in the crystal structure. In this way, the predicted position of the N-bound CH[3] group of dimethyl Lys^4 falls exactly in front of the N-5 atom of the flavin. This type of substrate-binding geometry is similar to that found in other flavin-dependent oxidases and is fully consistent with an oxidative attack of the flavin on the N–CH[3] group of the substrate leading to the formation of an NH=CH[2] imine that is then hydrolyzed to generate the demethylated Lys^4 and formaldehyde.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 20070-20074) copyright 2007.