8Z7C | pdb_00008z7c

Structure of G9a in complex with compound 7i

PDB DOI: https://doi.org/10.2210/pdb8Z7C/pdb

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

Deposited: 2024-04-20 Released: 2025-01-22
Deposition Author(s): Niwa, H., Shirai, F., Sato, S., Nishigaya, Y., Ihara, K., Shirouzu, M., Umehara, T.
Funding Organization(s): Japan Society for the Promotion of Science (JSPS)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.52 ?
R-Value Free:
0.196 (Depositor), 0.197 (DCC)
R-Value Work:
0.174 (Depositor), 0.176 (DCC)
R-Value Observed:
0.175 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.0 of the entry. See complete history.

Literature

Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment.

Nishigaya, Y., Takase, S., Sumiya, T., Sato, T., Niwa, H., Sato, S., Nakata, A., Matsuoka, S., Maemoto, Y., Hashimoto, N., Namie, R., Honma, T., Umehara, T., Shirouzu, M., Koyama, H., Yoshida, M., Ito, A., Shirai, F.

(2024) Bioorg Med Chem Lett 110: 129856-129856

PubMed: 38914346 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2024.129856
Primary Citation of Related Structures:
8Z7C, 8Z7D, 8Z7E

PubMed Abstract:
The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC ₅₀?=?0.024?μM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner.

Organizational Affiliation

Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co. Ltd., 1848 Nogi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: yousuke.nishigaya@mb.kyorin-pharm.co.jp.

Macromolecule Content

Total Structure Weight: 67.54 kDa
Atom Count: 5,060
Modeled Residue Count: 533
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
A1L07 (Subject of Investigation/LOI) Query on A1L07 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]	3,6,6-trimethyl-~{N}-[(2~{S})-1-[[4-(1-methylpiperidin-4-yl)oxyphenyl]amino]-1-oxidanylidene-hexan-2-yl]-4-oxidanylidene-5,7-dihydro-1~{H}-indole-2-carboxamide C₃₀ H₄₂ N₄ O₄ SANTZUMQHHSQMN-QHCPKHFHSA-N		Interactions Focus chain H [auth A] Focus chain N [auth B] Interactions & Density Focus chain H [auth A] Focus chain N [auth B]
SFG Query on SFG 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]	SINEFUNGIN C₁₅ H₂₃ N₇ O₅ LMXOHSDXUQEUSF-YECHIGJVSA-N		Interactions Focus chain G [auth A] Focus chain M [auth B] Interactions & Density Focus chain G [auth A] Focus chain M [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain K [auth B] SDF format, chain C [auth A] SDF format, chain L [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] MOL2 format, chain C [auth A] MOL2 format, chain L [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B] mmCIF format, chain C [auth A] mmCIF format, chain L [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]