8Z33 | pdb_00008z33

Crystal Structure of HIF-PHD2 in complex with compound 4

PDB DOI: https://doi.org/10.2210/pdb8Z33/pdb

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

Deposited: 2024-04-14 Released: 2025-02-26
Deposition Author(s): Ito, S., Baba, D., Fukuda, T., Tanaka, N.
Funding Organization(s): Not funded

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.60 Å
R-Value Free:
0.249 (Depositor), 0.259 (DCC)
R-Value Work:
0.202 (Depositor), 0.212 (DCC)
R-Value Observed:
0.206 (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

Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.

Fukuda, T., Kuribayashi, T., Takano, R., Sasaki, K., Tsuji, T., Niitsu, Y., Ishii, K., Hashimoto, M., Baba, D., Ito, S., Tanaka, N.

(2024) Bioorg Med Chem Lett 108: 129799-129799

PubMed: 38754564 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2024.129799
Primary Citation of Related Structures:
8Z31, 8Z32, 8Z33, 8Z35

PubMed Abstract:
Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.

Organizational Affiliation

R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: fukuda.takeshi.zv@daiichisankyo.co.jp.

Macromolecule Content

Total Structure Weight: 56.48 kDa
Atom Count: 3,407
Modelled Residue Count: 419
Deposited Residue Count: 494
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Egl nine homolog 1	A, B	247	Homo sapiens	Mutation(s): 0 Gene Names: EGLN1, C1orf12, PNAS-118, PNAS-137 EC: 1.14.11.29
UniProt & NIH Common Fund Data Resources
Find proteins for Q9GZT9 (Homo sapiens) Explore Q9GZT9 Go to UniProtKB: Q9GZT9
PHAROS: Q9GZT9 GTEx: ENSG00000135766
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9GZT9
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
A1L0W (Subject of Investigation/LOI) Query on A1L0W Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain H [auth B] MOL2 format, chain E [auth A] MOL2 format, chain H [auth B] mmCIF format, chain E [auth A] mmCIF format, chain H [auth B]	E [auth A], H [auth B]	2-[[6-[2-(4-fluorophenyl)ethyl]-2-methyl-5-oxidanyl-pyrimidin-4-yl]carbonylamino]ethanoic acid C₁₆ H₁₆ F N₃ O₄ OCRDRHRUSCHDBJ-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain H [auth B] Interactions & Density Focus chain E [auth A] Focus chain H [auth B]
FE2 Query on FE2 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain F [auth B] MOL2 format, chain C [auth A] MOL2 format, chain F [auth B] mmCIF format, chain C [auth A] mmCIF format, chain F [auth B]	C [auth A], F [auth B]	FE (II) ION Fe CWYNVVGOOAEACU-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain F [auth B] Interactions & Density Focus chain C [auth A] Focus chain F [auth B]
F Query on F Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain G [auth B] MOL2 format, chain D [auth A] MOL2 format, chain G [auth B] mmCIF format, chain D [auth A] mmCIF format, chain G [auth B]	D [auth A], G [auth B]	FLUORIDE ION F KRHYYFGTRYWZRS-UHFFFAOYSA-M		Interactions Focus chain D [auth A] Focus chain G [auth B] Interactions & Density Focus chain D [auth A] Focus chain G [auth B]