4JZR

Structure of Prolyl Hydroxylase Domain-containing Protein (PHD) with Inhibitors

Summary for 4JZR

• Entry DOI: 10.2210/pdb4jzr/pdb
• Descriptor: Egl nine homolog 1, NICKEL (II) ION, 2-(biphenyl-4-yl)-8-[(1-methyl-1H-imidazol-2-yl)methyl]-2,8-diazaspiro[4.5]decan-1-one, ... (5 entities in total)
• Functional Keywords: prolyl hydroxylase, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9GZT9
• Total number of polymer chains: 1
• Total formula weight: 24751.79

Authors

Ma, Y.,Yang, L. (deposition date: 2013-04-03, release date: 2013-10-30, Last modification date: 2024-10-16)

Primary citation

Deng, G.,Zhao, B.,Ma, Y.,Xu, Q.,Wang, H.,Yang, L.,Zhang, Q.,Guo, T.B.,Zhang, W.,Jiao, Y.,Cai, X.,Zhang, J.,Liu, H.,Guan, X.,Lu, H.,Xiang, J.,Elliott, J.D.,Lin, X.,Ren, F.
Novel complex crystal structure of prolyl hydroxylase domain-containing protein 2 (PHD2): 2,8-Diazaspiro[4.5]decan-1-ones as potent, orally bioavailable PHD2 inhibitors
Bioorg.Med.Chem., 21:6349-6358, 2013

PubMed Abstract: 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 π-cation interaction with Arg322, a π-π stacking with Trp389, and a π-π 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.

PubMed: 24055079
DOI: 10.1016/j.bmc.2013.08.046

Experimental method

X-RAY DIFFRACTION (2.1 Å)