PDBsum entry 3zms

Oxidoreductase/peptide

PDB id: 3zms

Contents

Protein chains

665 a.a.

133 a.a.

Ligands

PRO-ARG-GLY-PHE-LEU-VAL-LYS-ARG

FAD

PDB id:

3zms

Name:

Oxidoreductase/peptide

Title:

Lsd1-corest in complex with insm1 peptide

Structure:

Lysine-specific histone demethylase 1a. Chain: a. Synonym: lds1, braf35-hdac complex protein bhc110, flavin-containing amine oxidase domain-containing protein 2. Engineered: yes. Rest corepressor 1. Chain: b. Synonym: protein corest. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

2.96Å R-factor: 0.215 R-free: 0.227

Authors:

M.Tortorici,M.T.Borrello,M.Tardugno,L.R.Chiarelli,S.Pilotto, G.Ciossani,N.A.Vellore,J.Cowan,M.O'Connell,A.Mai,R.Baron,A.Ganesan, A.Mattevi

Key ref:

M.Tortorici et al. (2013). Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase. Acs Chem Biol, 8, 1677-1682. PubMed id: 23721412 DOI: 10.1021/cb4001926

Date:

12-Feb-13 Release date: 12-Jun-13

Protein chain

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

Seq: 852 a.a.

Struc: 665 a.a.

Protein chain

Q9UKL0  (RCOR1_HUMAN) -  REST corepressor 1 from Homo sapiens

Seq: 485 a.a.

Struc: 133 a.a.

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

N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + 2 × A + 2 × H2O = L-lysyl(4)- [histone H3] + 2 × formaldehyde (Bound ligand (Het Group name = GLY) matches with 50.00% similarity) + 2 × AH2

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

Key reference

DOI no: 10.1021/cb4001926

Acs Chem Biol 8:1677-1682 (2013)

PubMed id: 23721412

Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase.

M.Tortorici, M.T.Borrello, M.Tardugno, L.R.Chiarelli, S.Pilotto, G.Ciossani, N.A.Vellore, S.G.Bailey, J.Cowan, M.O'Connell, S.J.Crabb, G.Packham, A.Mai, R.Baron, A.Ganesan, A.Mattevi.

ABSTRACT

The combinatorial assembly of protein complexes is at the heart of chromatin biology. Lysine demethylase LSD1(KDM1A)/CoREST beautifully exemplifies this concept. The active site of the enzyme tightly associates to the N-terminal domain of transcription factors of the SNAIL1 family, which therefore can competitively inhibit the binding of the N-terminal tail of the histone substrate. Our enzymatic, crystallographic, spectroscopic, and computational studies reveal that LSD1/CoREST can bind to a hexapeptide derived from the SNAIL sequence through recognition of a positively charged α-helical turn that forms upon binding to the enzyme. Variations in sequence and length of this six amino acid ligand modulate affinities enabling the same binding site to differentially interact with proteins that exert distinct biological functions. The discovered short peptide inhibitors exhibit antiproliferative activities and lay the foundation for the development of peptidomimetic small molecule inhibitors of LSD1.