PDBsum entry 4xbf

Oxidoreductase/transcription/RNA

PDB id: 4xbf

Contents

Protein chains

666 a.a.

133 a.a.

DNA/RNA

Ligands

FAD

SO4 ×5

GOL

Waters ×23

PDB id:

4xbf

Name:

Oxidoreductase/transcription/RNA

Title:

Structure of lsd1:corest in complex with ssrna

Structure:

Lysine-specific histone demethylase 1a. Chain: a. Fragment: unp residues 171-836. Synonym: braf35-hdac complex protein bhc110,flavin-containing amine oxidase domain-containing protein 2. Engineered: yes. Other_details: recombinant plasmid (residues 171-852). Rest corepressor 1. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kdm1a, aof2, kdm1, kiaa0601, lsd1. Expressed in: escherichia coli. Expression_system_taxid: 469008. Gene: rcor1, kiaa0071, rcor. Synthetic: yes. Organism_taxid: 9606

Resolution:

2.80Å R-factor: 0.202 R-free: 0.227

Authors:

Z.Luka,L.V.Loukachevitch,W.J.Martin,C.Wagner,N.J.Reiter

Key ref:

A.Hirschi et al. (2016). G-quadruplex RNA binding and recognition by the lysine-specific histone demethylase-1 enzyme. Rna, 22, 1250-1260. PubMed id: 27277658

Date:

16-Dec-14 Release date: 27-Apr-16

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.

DNA/RNA chain

U-U-A-G-G 5 bases

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

Rna 22:1250-1260 (2016)

PubMed id: 27277658

G-quadruplex RNA binding and recognition by the lysine-specific histone demethylase-1 enzyme.

A.Hirschi, W.J.Martin, Z.Luka, L.V.Loukachevitch, N.J.Reiter.

ABSTRACT

Lysine-specific histone demethylase 1 (LSD1) is an essential epigenetic regulator in metazoans and requires the co-repressor element-1 silencing transcription factor (CoREST) to efficiently catalyze the removal of mono- and dimethyl functional groups from histone 3 at lysine positions 4 and 9 (H3K4/9). LSD1 interacts with over 60 regulatory proteins and also associates with lncRNAs (TERRA, HOTAIR), suggesting a regulatory role for RNA in LSD1 function. We report that a stacked, intramolecular G-quadruplex (GQ) forming TERRA RNA (GG[UUAGGG]8UUA) binds tightly to the functional LSD1-CoREST complex (Kd ≈ 96 nM), in contrast to a single GQ RNA unit ([UUAGGG]4U), a GQ DNA ([TTAGGG]4T), or an unstructured single-stranded RNA. Stabilization of a parallel-stranded GQ RNA structure by monovalent potassium ions (K(+)) is required for high affinity binding to the LSD1-CoREST complex. These data indicate that LSD1 can distinguish between RNA and DNA as well as structured versus unstructured nucleotide motifs. Further, cross-linking mass spectrometry identified the primary location of GQ RNA binding within the SWIRM/amine oxidase domain (AOD) of LSD1. An ssRNA binding region adjacent to this GQ binding site was also identified via X-ray crystallography. This RNA binding interface is consistent with kinetic assays, demonstrating that a GQ-forming RNA can serve as a noncompetitive inhibitor of LSD1-catalyzed demethylation. The identification of a GQ RNA binding site coupled with kinetic data suggests that structured RNAs can function as regulatory molecules in LSD1-mediated mechanisms.