4JZR: Structure Of Prolyl Hydroxylase Domain-containing Protein (phd) With Inhibitors

We have discovered a novel complex crystal structure of the PHD2 enzyme with its inhibitor, the 2,8-diazaspiro[4.5]decan-1-one analogue 4b. The widely reported salt bridge between Arg383 of the enzyme and its inhibitors in all complex structures published thus far was not observed in our case. In our complex structure compound 4b forms several novel interactions with the enzyme, which include a hydrogen bond with Arg322, a pi-cation interaction with Arg322, a pi-pi stacking with Trp389, and a pi-pi stacking with His313. Guided by the structural information, SAR studies were performed on the 2,8-diazaspiro[4.5]decan-1-one series leading to the discovery of compound 9p with high potency and good oral pharmacokinetic profile in mice.
PDB ID: 4JZRDownload
MMDB ID: 114721
PDB Deposition Date: 2013/4/3
Updated in MMDB: 2013/10
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 4JZR: monomeric; determined by author and by software (PISA)
Molecular Components in 4JZR
Label Count Molecule
Protein (1 molecule)
EGL Nine Homolog 1(Gene symbol: EGLN1)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB