Crystal structures of Apo and GMP bound hypoxanthine–guanine phosphoribosyltransferase from Legionella pneumophila and the implications in gouty arthritis

Abstract Hypoxanthine–guanine phosphoribosyltransferase (HGPRT) (EC 2.4.2.8) reversibly catalyzes the transfer of the 5-phophoribosyl group from 5-phosphoribosyl-alpha-1-pyrophosphate (PRPP) to hypoxanthine or guanine to form inosine monophosphate (IMP) or guanosine monophosphate (GMP) in the purine salvage pathway. To investigate the catalytic mechanism of this enzyme in the intracellular pathogen Legionella pneumophila , we determined the crystal structures of the L. pneumophila HGPRT ( Lp HGPRT) both in its apo-form and in complex with GMP. The structures reveal that Lp HGPRT comprises a core domain and a hood domain which are packed together to create a cavity for GMP-binding and the enzymatic catalysis. The binding of GMP induces conformational changes of the stable loop II. This new binding site is closely related to the Gout arthritis-linked human HGPRT mutation site (Ser103Arg). Finally, these structures of Lp HGPRT provide insights into the catalytic mechanism of HGPRT.