PDBsum entry 6kgo

Oxidoreductase

PDB id: 6kgo

Contents

Protein chain

647 a.a.

Ligands

GOL ×6

TLA

DJ0-FAD

Waters ×190

PDB id:

6kgo

Name:

Oxidoreductase

Title:

Lsd1-s2157 five-membered ring adduct model

Structure:

Lysine-specific histone demethylase 1a. Chain: a. Synonym: braf35-hdac complex protein bhc110,flavin-containing amine oxidase domain-containing protein 2. Engineered: yes. Other_details: sf file contains friedel pairs.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kdm1a, aof2, kdm1, kiaa0601, lsd1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.25Å R-factor: 0.175 R-free: 0.204

Authors:

H.Niwa,S.Sato,T.Umehara

Key ref:

H.Niwa et al. (2020). Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors. ChemMedChem, 15, 787-793. PubMed id: 32166890 DOI: 10.1002/cmdc.202000014

Date:

12-Jul-19 Release date: 25-Mar-20

Protein chain

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

Seq: 852 a.a.

Struc: 647 a.a.

Enzyme reactions

• Enzyme class: 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: 10.1002/cmdc.202000014

ChemMedChem 15:787-793 (2020)

PubMed id: 32166890

Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors.

H.Niwa, S.Sato, N.Handa, T.Sengoku, T.Umehara, S.Yokoyama.

ABSTRACT

Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD)-dependent enzyme that catalyzes the demethylation of histone H3 and regulates gene expression. Because it is implicated in the regulation of diseases such as acute myeloid leukemia, potent LSD1-specific inhibitors have been pursued. Trans-2-phenylcyclopropylamine (2-PCPA)-based inhibitors featuring substitutions on the amino group have emerged, with sub-micromolar affinities toward LSD1 and high selectivities over monoamine oxidases (MAOs). We synthesized two N-alkylated 2-PCPA-based LSD1 inhibitors, S2116 and S2157, based on the previously developed S2101. S2116 and S2157 exhibited enhanced potency for LSD1 by 2.0- to 2.6-fold, as compared with S2101. In addition, they exhibited improved selectivity over MAOs. Structural analyses of LSD1 co-crystallized with S2101, S2116, S2157, or another N-alkylated inhibitor (FCPA-MPE) confirmed that the N-substituents enhance the potency of a 2-PCPA-based inhibitor of LSD1, without constituting the adduct formed with FAD.