6QGV

HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with a Spiro[4.5]decanone inhibitor (JPHM-2-167)

PDB DOI: https://doi.org/10.2210/pdb6QGV/pdb

Classification: OXIDOREDUCTASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2019-01-13 Released: 2020-02-05
Deposition Author(s): Chowdhury, R., Holt-Martyn, J.P., Rahman, M.Z., Schofield, C.J.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.40 Å
R-Value Free: 0.172
R-Value Work: 0.157
R-Value Observed: 0.158

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Studies on spiro[4.5]decanone prolyl hydroxylase domain inhibitors.

Holt-Martyn, J.P., Tumber, A., Rahman, M.Z., Lippl, K., Figg Jr., W., McDonough, M.A., Chowdhury, R., Schofield, C.J.

(2019) Medchemcomm 10: 500-504

PubMed: 31057728 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1039/c8md00548f
Primary Citation of Related Structures:
6QGV

PubMed Abstract:
The 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are targets for treatment of anaemia and other ischaemia related diseases. PHD inhibitors are in clinical trials; however, the number of reported templates for PHD inhibition is limited. We report structure-activity relationship and crystallographic studies on spiro[4.5]decanone containing PHD inhibitors. Together with other studies, our results reveal spiro[4.5]decanones as useful templates for generation of potent and selective 2OG oxygenase inhibitors.

Organizational Affiliation

Department of Chemistry , University of Oxford , Chemistry Research Laboratory , 12 Mansfield Road , Oxford , OX1 3TA , UK . Email: christopher.schofield@chem.ox.ac.uk.

Macromolecule Content

Total Structure Weight: 26.94 kDa
Atom Count: 1,884
Modelled Residue Count: 198
Deposited Residue Count: 233
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	233	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 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
J2H Query on J2H Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	8-[(3-methylpyridin-2-yl)methyl]-3-(4-phenylphenyl)-1-pyrimidin-2-yl-1,3,8-triazaspiro[4.5]decane-2,4-dione C₃₀ H₂₈ N₆ O₂ FIMHRJKSKVXMEB-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain F [auth A]	F [auth A], G [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain F [auth A] Focus chain G [auth A] Interactions & Density Focus chain F [auth A] Focus chain G [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
IPA Query on IPA Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	ISOPROPYL ALCOHOL C₃ H₈ O KFZMGEQAYNKOFK-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]
MN Query on MN Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	MANGANESE (II) ION Mn WAEMQWOKJMHJLA-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
J2H	BindingDB: 6QGV	IC50: 2.1 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.40 Å
R-Value Free: 0.172
R-Value Work: 0.157
R-Value Observed: 0.158
Space Group: H 3 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 120.065	α = 90
b = 120.065	β = 90
c = 86.563	γ = 120

Software Package:

Software Name	Purpose
PHENIX	refinement
DIALS	data reduction
SCALA	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2020-02-05

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2020-02-05
Type: Initial release
Version 1.1: 2021-01-20
Changes: Database references, Refinement description
Version 1.2: 2021-02-24
Changes: Database references
Version 1.3: 2024-01-24
Changes: Data collection, Database references, Refinement description