PDBsum entry 4z1v

Oxidoreductase

PDB id: 4z1v

Contents

Protein chain

341 a.a.

Ligands

OGA

_NO

PEG

SO4 ×5

Metals

_FE

Waters ×99

PDB id:

4z1v

Name:

Oxidoreductase

Title:

Structure of factor inhibiting hif (fih) in complex with fe, no, and nog

Structure:

Hypoxia-inducible factor 1-alpha inhibitor. Chain: a. Synonym: factor inhibiting hif-1,fih-1,hypoxia-inducible factor asparagine hydroxylase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hif1an, fih1. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.10Å R-factor: 0.195 R-free: 0.240

Authors:

C.Y.Taabazuing,S.C.Garman,M.J.Knapp

Key ref:

C.Y.Taabazuing et al. (2016). Substrate Promotes Productive Gas Binding in the α-Ketoglutarate-Dependent Oxygenase FIH. Biochemistry, 55, 277-286. PubMed id: 26727884 DOI: 10.1021/acs.biochem.5b01003

Date:

27-Mar-15 Release date: 13-Jan-16

Protein chain

Q9NWT6  (HIF1N_HUMAN) -  Hypoxia-inducible factor 1-alpha inhibitor from Homo sapiens

Seq: 349 a.a.

Struc: 342 a.a.

Enzyme reactions

• Enzyme class 1: E.C.1.14.11.30 - hypoxia-inducible factor-asparagine dioxygenase.
• Reaction: L-asparaginyl-[hypoxia-inducible factor alpha subunit] + 2-oxoglutarate + O2 = (3S)-3-hydroxy-L-asparaginyl-[hypoxia-inducible factor alpha subunit] + succinate + CO2
• Cofactor: Fe(2+); L-ascorbate

Fe(2+) L-ascorbate (Bound ligand (Het Group name = PEG) matches with 58.33% similarity)

• Enzyme class 2: E.C.1.14.11.n4 - ?????

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.biochem.5b01003

Biochemistry 55:277-286 (2016)

PubMed id: 26727884

Substrate Promotes Productive Gas Binding in the α-Ketoglutarate-Dependent Oxygenase FIH.

C.Y.Taabazuing, J.Fermann, S.Garman, M.J.Knapp.

ABSTRACT

The Fe(2+)/α-ketoglutarate (αKG)-dependent oxygenases use molecular oxygen to conduct a wide variety of reactions with important biological implications, such as DNA base excision repair, histone demethylation, and the cellular hypoxia response. These enzymes follow a sequential mechanism in which O2 binds and reacts after the primary substrate binds, making those structural factors that promote productive O2 binding central to their chemistry. A large challenge in this field is to identify strategies that engender productive turnover. Factor inhibiting HIF (FIH) is a Fe(2+)/αKG-dependent oxygenase that forms part of the O2 sensing machinery in human cells by hydroxylating the C-terminal transactivation domain (CTAD) found within the HIF-1α protein. The structure of FIH was determined with the O2 analogue NO bound to Fe, offering the first direct insight into the gas binding geometry in this enzyme. Through a combination of density functional theory calculations, {FeNO}(7) electron paramagnetic resonance spectroscopy, and ultraviolet-visible absorption spectroscopy, we demonstrate that CTAD binding stimulates O2 reactivity by altering the orientation of the bound gas molecule. Although unliganded FIH binds NO with moderate affinity, the bound gas can adopt either of two orientations with similar stability; upon CTAD binding, NO adopts a single preferred orientation that is appropriate for supporting oxidative decarboxylation. Combined with other studies of related enzymes, our data suggest that substrate-induced reorientation of bound O2 is the mechanism utilized by the αKG oxygenases to tightly couple O2 activation to substrate hydroxylation.