PDBsum entry 6f6d

Oxidoreductase

PDB id: 6f6d

Contents

Protein chains

450 a.a.

17 a.a.

Ligands

AKG

TBU ×3

Metals

_FE

_ZN

Waters ×453

PDB id:

6f6d

Name:

Oxidoreductase

Title:

The catalytic domain of kdm6b in complex with h3(17-33)k18ia21m peptide

Structure:

Lysine-specific demethylase 6b. Chain: a. Synonym: jmjc domain-containing protein 3,jumonji domain-containing protein 3,lysine demethylase 6b. Engineered: yes. Histone 3 peptide h3(17-33)k18ia21m. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kdm6b, jmjd3, kiaa0346. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.82Å R-factor: 0.167 R-free: 0.214

Authors:

S.E.Jones,L.Olsen,M.Gajhede

Key ref:

S.E.Jones et al. (2018). Structural Basis of Histone Demethylase KDM6B Histone 3 Lysine 27 Specificity. Biochemistry, 57, 585-592. PubMed id: 29220567 DOI: 10.1021/acs.biochem.7b01152

Date:

05-Dec-17 Release date: 17-Oct-18

Protein chain

O15054  (KDM6B_HUMAN) -  Lysine-specific demethylase 6B from Homo sapiens

Seq: 1643 a.a.

Struc: 450 a.a.

Protein chain

P68431  (H31_HUMAN) -  Histone H3.1 from Homo sapiens

Seq: 136 a.a.

Struc: 17 a.a.*

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

Enzyme reactions

• Enzyme class: Chain A: E.C.1.14.11.68 - [histone H3]-trimethyl-L-lysine(27) demethylase.
• Reaction: N₆,N₆,N₆-trimethyl-L-lysyl₂₇-[histone H3] + 2 2-oxoglutarate + 2 O2 = N₆-methyl-L-lysyl₂₇-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2

N(6),N(6),N(6)-trimethyl-L-lysyl(27)-[histone H3] (Bound ligand (Het Group name = AKG) corresponds exactly) + 2 × 2-oxoglutarate + 2 × O2 = N(6)-methyl-L-lysyl(27)-[histone H3] + 2 × formaldehyde (Bound ligand (Het Group name = TBU) matches with 40.00% similarity) + 2 × succinate + 2 × CO2

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

reference

DOI no: 10.1021/acs.biochem.7b01152

Biochemistry 57:585-592 (2018)

PubMed id: 29220567

Structural Basis of Histone Demethylase KDM6B Histone 3 Lysine 27 Specificity.

S.E.Jones, L.Olsen, M.Gajhede.

ABSTRACT

KDM subfamily 6 enzymes KDM6A and KDM6B specifically catalyze demethylation of di- and trimethylated lysine on histone 3 lysine 27 (H3K27me3/2) and play an important role in repression of developmental genes. Despite identical amino acid sequence in the immediate surroundings of H3K9me3/2 (ARKS), the enzymes do not catalyze demethylation of this general marker of repression. To address this question for KDM6B, we used computational methods to identify H3(17-33)-derived peptides with improved binding affinity that would allow co-crystallization with the catalytic core of human KDM6B (ccKDM6B). A total of five peptides were identified, and their IC₅₀ values were determined in a matrix-assisted laser desorption ionization time-of-flight-based assay. Despite none of the peptides showing affinity significantly higher than that of the H3(17-33) peptide, it was possible to co-crystallize ccKDM6B with a H3(17-33)A21M peptide. This structure reveals the interactions between the KDM6B zinc binding domain and the H3(17-23) region. Although KDM6A and KDM6B differ in primary sequence, particularly in the H3L20 binding pocket of the zinc binding domains, where two histidines in KDM6A have been replaced by a glutamate and a tyrosine, they bind H3(17-23) in a very similar fashion. This structure shows that KDM6B, in analogy with KDM6A, also uses the zinc binding domain to achieve H3K27me3/me2 specificity. The histidine to glutamine substitution at amino acid position 1564 in the KDM6B zinc binding domain can further explain why KDM6B binds substrates with an affinity higher than that of KDM6A.