4wb9

Human ALDH1A1 complexed with NADHHuman ALDH1A1 complexed with NADH

Structural highlights 4wb9 is a 1 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 2.07Å Ligands: , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AL1A1_HUMAN Binds free retinal and cellular retinol-binding protein-bound retinal. Can convert/oxidize retinaldehyde to retinoic acid (By similarity). Publication Abstract from PubMed The human aldehyde dehydrogenase (ALDH) superfamily consists of at least 19 enzymes that metabolize endogenous and exogenous aldehydes. Currently, there are no commercially available inhibitors that target ALDH1A1 but have little to no effect on the structurally and functionally similar ALDH2. Here we present the first human ALDH1A1 structure, as the apo-enzyme and in complex with its cofactor NADH to a resolution of 1.75 and 2.1A, respectfully. Structural comparisons of the cofactor binding sites in ALDH1A1 with other closely related ALDH enzymes illustrate a high degree of similarity. In order to minimize discovery of compounds that inhibit both isoenzymes by interfering with their conserved cofactor binding sites, this study reports the use of an in vitro, NAD+-independent, esterase-based high-throughput screen (HTS) of 64,000 compounds to discover novel, selective inhibitors of ALDH1A1. We describe 256 hits that alter the esterase activity of ALDH1A1. The effects on aldehyde oxidation of 67 compounds were further analyzed, with 30 selectively inhibiting ALDH1A1 compared to ALDH2 and ALDH3A1. One compound inhibited ALDH1A1 and ALDH2, while another inhibited ALDH1A1, ALDH2, and the more distantly related ALDH3A1. The results presented here indicate that this in vitro enzyme activity screening protocol successfully identified ALDH1A1 inhibitors with a high degree of isoenzyme selectivity. The compounds identified via this screen plus the screening methodology itself represent a starting point for the development of highly potent and selective inhibitors of ALDH1A1 that may be utilized to better understand the role of this enzyme in both normal and disease states. Development of a high-throughput in vitro assay to identify selective inhibitors for human ALDH1A1.,Morgan CA, Hurley TD Chem Biol Interact. 2014 Nov 4. pii: S0009-2797(14)00326-3. doi:, 10.1016/j.cbi.2014.10.028. PMID:25450233 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aldehyde dehydrogenase 3D structures

spinqualitylabelsall models 4wb9, resolution 2.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image