5fhz

From Proteopedia

Human aldehyde dehydrogenase 1A3 complexed with NAD(+) and retinoic acid

PDB ID 5fhz

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Structural highlights

5fhz is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.9Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AL1A3_HUMAN Isolated anophthalmia - microphthalmia. The disease is caused by mutations affecting the gene represented in this entry.

Function

AL1A3_HUMAN Recognizes as substrates free retinal and cellular retinol-binding protein-bound retinal. Seems to be the key enzyme in the formation of an RA gradient along the dorso-ventral axis during the early eye development and also in the development of the olfactory system (By similarity).

Publication Abstract from PubMed

The aldehyde dehydrogenase family 1 member A3 (ALDH1A3) catalyzes the oxidation of retinal to the pleiotropic factor retinoic acid using NAD+. The level of ALDHs enzymatic activity has been used as a cancer stem cell marker and seems to correlate with tumour aggressiveness. Elevated ALDH1A3 expression in mesenchymal glioma stem cells highlights the potential of this isozyme as a prognosis marker and drug target. Here we report the first crystal structure of human ALDH1A3 complexed with NAD+ and the product all-trans retinoic acid (REA). The tetrameric ALDH1A3 folds into a three domain-based architecture highly conserved along the ALDHs family. The structural analysis revealed two different and coupled conformations for NAD+ and REA that we propose to represent two snapshots along the catalytic cycle. Indeed, the isoprenic moiety of REA points either toward the active site cysteine, or moves away adopting the product release conformation. Although ALDH1A3 shares high sequence identity with other members of the ALDH1A family, our structural analysis revealed few peculiar residues in the 1A3 isozyme active site. Our data provide information into the ALDH1As catalytic process and can be used for the structure-based design of selective inhibitors of potential medical interest.

Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD+ and retinoic acid.,Moretti A, Li J, Donini S, Sobol RW, Rizzi M, Garavaglia S Sci Rep. 2016 Oct 19;6:35710. doi: 10.1038/srep35710. PMID:27759097^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Moretti A, Li J, Donini S, Sobol RW, Rizzi M, Garavaglia S. Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD+ and retinoic acid. Sci Rep. 2016 Oct 19;6:35710. doi: 10.1038/srep35710. PMID:27759097 doi:http://dx.doi.org/10.1038/srep35710