PDBsum entry 4gut

Oxidoreductase

PDB id

4gut

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Contents

			Protein chains

					740 a.a.


					12 a.a.

			Ligands

					FAD


					GOL ×2


					PGE

			Metals

					_ZN ×3

			Waters ×346

PDB id:

4gut

Links

Name:

Oxidoreductase

Title:

Crystal structure of lsd2-npac

Structure:

Lysine-specific histone demethylase 1b. Chain: a. Fragment: unp residues 51-822. Synonym: lsd2, flavin-containing amine oxidase domain-containing protein 1, lysine-specific histone demethylase 2. Engineered: yes. Putative oxidoreductase glyr1. Chain: b. Fragment: unp residues 152-268.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lsd2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Gene: glyr1. Expressed in: escherichia coli.

Resolution:

2.00Å

R-factor:

0.197

R-free:

0.207

Authors:

F.Chen,Z.Dong,J.Fang,Y.Yang,Z.Li,Y.Xu,H.Yang,P.Wang,R.Fang,Y.Shi,Y.Xu

Key ref:

R.Fang et al. (2013). LSD2/KDM1B and its cofactor NPAC/GLYR1 endow a structural and molecular model for regulation of H3K4 demethylation. Mol Cell, 49, 558-570. PubMed id: 23260659

Date:

29-Aug-12

Release date:

16-Jan-13

PROCHECK

	Headers

	References

Protein chain

Q8NB78 (KDM1B_HUMAN) - Lysine-specific histone demethylase 2 from Homo sapiens

Seq: Struc:

Seq: Struc:					822 a.a. 740 a.a.*

Protein chain

Q49A26 (GLYR1_HUMAN) - Cytokine-like nuclear factor N-PAC from Homo sapiens

Seq: Struc:

Seq: Struc:					553 a.a. 12 a.a.

Key:

PfamA domain

Secondary structure

* PDB and UniProt seqs differ at 4 residue positions (black crosses)



		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.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

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	+	2 × AH2

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

Key reference

	Mol Cell 49:558-570 (2013)
PubMed id: 23260659

LSD2/KDM1B and its cofactor NPAC/GLYR1 endow a structural and molecular model for regulation of H3K4 demethylation.
R.Fang, F.Chen, Z.Dong, D.Hu, A.J.Barbera, E.A.Clark, J.Fang, Y.Yang, P.Mei, M.Rutenberg, Z.Li, Y.Zhang, Y.Xu, H.Yang, P.Wang, M.D.Simon, Q.Zhou, J.Li, M.P.Marynick, X.Li, H.Lu, U.B.Kaiser, R.E.Kingston, Y.Xu, Y.G.Shi.

ABSTRACT

Dynamic regulation of histone methylation represents a fundamental epigenetic mechanism underlying eukaryotic gene regulation, yet little is known about how the catalytic activities of histone demethylases are regulated. Here, we identify and characterize NPAC/GLYR1 as an LSD2/KDM1b-specific cofactor that stimulates H3K4me1 and H3K4me2 demethylation. We determine the crystal structures of LSD2 alone and LSD2 in complex with the NPAC linker region in the absence or presence of histone H3 peptide, at resolutions of 2.9, 2.0, and 2.25 Å, respectively. These crystal structures and further biochemical characterization define a dodecapeptide of NPAC (residues 214-225) as the minimal functional unit for its cofactor activity and provide structural determinants and a molecular mechanism underlying the intrinsic cofactor activity of NPAC in stimulating LSD2-catalyzed H3K4 demethylation. Thus, these findings establish a model for how a cofactor directly regulates histone demethylation and will have a significant impact on our understanding of catalytic-activity-based epigenetic regulation.