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Crystal structures of Trypanosoma brucei hypoxanthine – guanine – xanthine phosphoribosyltransferase in complex with IMP , GMP and XMP
Author(s) -
Terán David,
Doleželová Eva,
Keough Dianne T.,
Hocková Dana,
Zíková Alena,
Guddat Luke W.
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14987
Subject(s) - trypanosoma brucei , hypoxanthine , phosphoribosyltransferase , chemistry , hypoxanthine guanine phosphoribosyltransferase , biochemistry , enzyme , gene , mutant
The 6‐oxopurine phosphoribosyltransferases ( PRT s) are drug targets for the treatment of parasitic diseases. This is due to the fact that parasites are auxotrophic for the 6‐oxopurine bases relying on salvage enzymes for the synthesis of their 6‐oxopurine nucleoside monophosphates. In Trypanosoma brucei, the parasite that is the aetiological agent for sleeping sickness, there are three 6‐oxopurine PRT isoforms. Two are specific for hypoxanthine and guanine, whilst the third, characterized here, uses all three naturally occurring bases with similar efficiency. Here, we have determined crystal structures for Tbr HGXPRT in complex with GMP , XMP and IMP to investigate the structural basis for substrate specificity. The results show that Y201 and E208, not commonly observed within the purine binding pocket of 6‐oxopurine PRT s, contribute to the versatility of this enzyme. The structures further show that a nearby water can act as an adaptor to facilitate the binding of XMP and GMP . When GMP binds, a water can accept a proton from the 2‐amino group but when XMP binds, the equivalent water can donate its proton to the 2‐oxo group. However, when IMP is bound, no water molecule is observed at that location. Database Coordinates and structure factors were submitted to the Protein Data Bank and have accession codes of 6 MXB , 6 MXC , 6 MXD and 6 MXG for the Tbr HGXPRT . XMP complex, Tbr HGXPRT . GMP complex, Tbr HGXPRT . IMP complex, and Tbr HGPRT . XMP complex, respectively.