5in3

Crystal structure of glucose-1-phosphate bound nucleotidylated human galactose-1-phosphate uridylyltransferase

spinqualitylabelsall models 5in3, resolution 1.73Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5in3 is a 2 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 1.73Å Ligands: EDO, G1P, H2U, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease GALT_HUMAN Classic galactosemia. The disease is caused by mutations affecting the gene represented in this entry. Function GALT_HUMAN Publication Abstract from PubMed Classic galactosemia is a potentially lethal disease caused by the dysfunction of galactose 1-phosphate uridylyltransferase (GALT). Over 300 disease-associated GALT mutations have been reported, with the majority being missense changes, although a better understanding of their underlying molecular effects has been hindered by the lack of structural information for the human enzyme. Here, we present the 1.9 A resolution crystal structure of human GALT (hGALT) ternary complex, revealing a homodimer arrangement that contains a covalent uridylylated intermediate and glucose-1-phosphate in the active site, as well as a structural zinc-binding site, per monomer. hGALT reveals significant structural differences from bacterial GALT homologues in metal ligation and dimer interactions, and therefore is a zbetter model for understanding the molecular consequences of disease mutations. Both uridylylation and zinc binding influence the stability and aggregation tendency of hGALT. This has implications for disease-associated variants where p.Gln188Arg, the most commonly detected, increases the rate of aggregation in the absence of zinc likely due to its reduced ability to form the uridylylated intermediate. As such our structure serves as a template in the future design of pharmacological chaperone therapies and opens new concepts about the roles of metal binding and activity in protein misfolding by disease-associated mutants. Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase.,McCorvie TJ, Kopec J, Pey AL, Fitzpatrick F, Patel D, Chalk R, Shrestha L, Yue WW Hum Mol Genet. 2016 Mar 22. pii: ddw091. PMID:27005423 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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