Crystal structure of the bifunctional enzyme phosphoribosyl isomerase A from Mycobacterium tuberculosis with bound light-controllable inhibitor.

The enzyme phosphoribosyl isomerase A from Mycobacterium tuberculosis (mtPriA) catalyzes two related reactions of bi- and monophosphorylated substrates within the histidine and tryptophan biosynthetic pathways. We have determined the crystal structure of mtPriA with a bound light-controllable 1,2-dithienylethene inhibitor (DTE LC6) at a resolution of 1.95 Å. DTE LC6 contains two terminal phosphate groups, and we found one inhibitor molecule (DTE LC6-1) simultaneously bound to the two known functional phosphate-binding sites of mtPriA. Unexpectedly, another inhibitor molecule (DTE LC6-2) was shown to bind to a hitherto unidentified third phosphate-binding site and thus bridges two crystallographic symmetry-related mtPriA proteins. Our study explains the previously reported inhibitory effect of DTE LC6 on the catalytic activity of mtPriA and raises the question of the significance of the third phosphate-binding site in mtPriA.