5L9V: HIF prolyl hydroxylase 2 (PHD2-R281C/P317C) cross-linked to HIF-1alpha NODD-L397C/D412C and N-oxalylglycine (NOG) (complex-1)

The response to hypoxia in animals involves the expression of multiple genes regulated by the alphabeta-hypoxia-inducible transcription factors (HIFs). The hypoxia-sensing mechanism involves oxygen limited hydroxylation of prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of HIFalpha isoforms, as catalysed by prolyl hydroxylases (PHD 1-3). Prolyl hydroxylation promotes binding of HIFalpha to the von Hippel-Lindau protein (VHL)-elongin B/C complex, thus signalling for proteosomal degradation of HIFalpha. We reveal that certain PHD2 variants linked to familial erythrocytosis and cancer are highly selective for CODD or NODD. Crystalline and solution state studies coupled to kinetic and cellular analyses reveal how wild-type and variant PHDs achieve ODD selectivity via different dynamic interactions involving loop and C-terminal regions. The results inform on how HIF target gene selectivity is achieved and will be of use in developing selective PHD inhibitors.
PDB ID: 5L9VDownload
MMDB ID: 142673
PDB Deposition Date: 2016/6/11
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 1.829  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 5L9V: dimeric; determined by software (PISA)
Molecular Components in 5L9V
Label Count Molecule
Proteins (2 molecules)
EGL Nine Homolog 1(Gene symbol: EGLN1)
Molecule annotation
Hypoxia-inducible Factor 1-alpha(Gene symbol: HIF1A)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB