Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase.

摘要: 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 majority being missense changes, although better understanding their underlying molecular effects has hindered lack structural information for human enzyme. Here, we present 1.9 A resolution crystal structure (hGALT) ternary complex, revealing homodimer arrangement that contains covalent uridylylated intermediate and glucose-1-phosphate in active site, as well zinc-binding per monomer. hGALT reveals significant differences from bacterial homologues metal ligation dimer interactions, therefore zbetter model consequences mutations. Both uridylylation zinc binding influence stability aggregation tendency hGALT. This implications variants where p.Gln188Arg, most commonly detected, increases rate absence likely due to its reduced ability form intermediate. As such our serves template future design pharmacological chaperone therapies opens new concepts about roles activity protein misfolding mutants.