Structure of HisF, a histidine biosynthetic protein from Pyrobaculum aerophilum

HisF (imidazole glycerol phosphate synthase) is an important branch-point e nzyme in the histidine biosynthetic pathway of microorganisms. Because of i ts potential relevance for structure-based drug design, the crystal structu re of HisF from the hyperthermophilic archaeon Pyrobaculum aerophilum has b een determined. The structure was determined by molecular replacement and r efined at 2.0 Angstrom resolution to a crystallographic R factor of 20.6% a nd a free R of 22.7%. The structure adopts a classic (beta/alpha)(8) barrel fold and has networks of surface salt bridges that may contribute to therm ostability. The active site is marked out by the presence of two bound phos phate ions and two glycerol molecules that delineate a long groove at one e nd of the (beta/alpha)(8) barrel. The two phosphate ions, 17 Angstrom apart , are bound to sequence-conserved structural motifs that seem likely to pro vide much of the specificity for the two phosphate groups of the HisF subst rate. The two glycerol molecules bind in the vicinity of other sequence-con served residues that are likely to be involved in binding and/or catalysis. Comparisons with the homologous HisF from Thermatoga maritima reveal a dis placed loop that may serve as a lid over the active site.