7DCF

Crystal structure of EHMT2 SET domain in complex with compound 10

PDB DOI: https://doi.org/10.2210/pdb7DCF/pdb

Classification: TRANSFERASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2020-10-26 Released: 2021-02-10
Deposition Author(s): Suzuki, M., Katayama, K.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.246
R-Value Work: 0.200
R-Value Observed: 0.202

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Discovery of DS79932728: A Potent, Orally Available G9a/GLP Inhibitor for Treating beta-Thalassemia and Sickle Cell Disease.

Katayama, K., Ishii, K., Terashima, H., Tsuda, E., Suzuki, M., Yotsumoto, K., Hiramoto, K., Yasumatsu, I., Torihata, M., Ishiyama, T., Muto, T., Katagiri, T.

(2021) ACS Med Chem Lett 12: 121-128

PubMed: 33488973 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.0c00572
Primary Citation of Related Structures:
7DCF

PubMed Abstract:
Therapeutic reactivation of the γ-globin genes for fetal hemoglobin (HbF) production is an attractive strategy for treating β-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently. It was revealed that tetrahydroazepine has versatility as a side chain in various skeletons. We ultimately obtained a promising aminoindole derivative (DS79932728), a potent and orally bioavailable G9a/GLP inhibitor that was found to induce γ-globin production in a phlebotomized cynomolgus monkey model. This work could facilitate the development of effective new approaches for treating β-thalassemia and sickle cell disease.

Organizational Affiliation

R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

Macromolecule Content

Total Structure Weight: 67.15 kDa
Atom Count: 4,532
Modelled Residue Count: 519
Deposited Residue Count: 566
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Histone-lysine N-methyltransferase EHMT2	A, B	283	Homo sapiens	Mutation(s): 0 Gene Names: EHMT2, BAT8, C6orf30, G9A, KMT1C, NG36 EC: 2.1.1 (PDB Primary Data), 2.1.1.367 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q96KQ7 (Homo sapiens) Explore Q96KQ7 Go to UniProtKB: Q96KQ7
PHAROS: Q96KQ7 GTEx: ENSG00000204371
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q96KQ7
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
SAM Query on SAM Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain M [auth B] MOL2 format, chain G [auth A] MOL2 format, chain M [auth B] mmCIF format, chain G [auth A] mmCIF format, chain M [auth B]	G [auth A], M [auth B]	S-ADENOSYLMETHIONINE C₁₅ H₂₂ N₆ O₅ S MEFKEPWMEQBLKI-FCKMPRQPSA-N		Interactions Focus chain G [auth A] Focus chain M [auth B] Interactions & Density Focus chain G [auth A] Focus chain M [auth B]
H30 (Subject of Investigation/LOI) Query on H30 Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain N [auth B] MOL2 format, chain H [auth A] MOL2 format, chain N [auth B] mmCIF format, chain H [auth A] mmCIF format, chain N [auth B]	H [auth A], N [auth B]	5'-methoxy-6'-(1-methyl-2,3,4,7-tetrahydroazepin-5-yl)spiro[cyclobutane-1,3'-indole]-2'-amine C₁₉ H₂₅ N₃ O VMVRYCYPSDCNEH-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain N [auth B] Interactions & Density Focus chain H [auth A] Focus chain N [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain L [auth B] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain K [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain L [auth B] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain L [auth B] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B]	C [auth A] D [auth A] E [auth A] F [auth A] I [auth B] C [auth A], D [auth A], E [auth A], F [auth A], I [auth B], J [auth B], K [auth B], L [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B]