Quadruple Space-Group Ambiguity Owing to Rotational and Translational Noncrystallographic Symmetry in Human Liver Fructose-1,6-Bisphosphatase

Fructose-1,6-bisphosphatase (FBPase) is a key regulator of gluconeogenesis and a potential drug target for type 2 diabetes. FBPase is a homotetramer of 222 symmetry with a major and a minor dimer interface. The dimers connectedviathe minor interface can rotate with respect to each other, leading to the inactive T-state and active R-state conformations of FBPase. Here, the first crystal structure of human liver FBPase in the R-state conformation is presented, determined at a resolution of 2.2 Å in a tetragonal setting that exhibits an unusual arrangement of noncrystallographic symmetry (NCS) elements. Self-Patterson function analysis and various intensity statistics revealed the presence of pseudo-translation and the absence of twinning. The space group isP41212, but structure determination was also possible in space groupsP43212,P4122 andP4322. All solutions have the same arrangement of threeC2-symmetric dimers spaced by 1/3 along an NCS axis parallel to thecaxis located at (1/4, 1/4,z), which is therefore invisible in a self-rotation function analysis. The solutions in the four space groups are related to one another and emulate a body-centred lattice. If all NCS elements were crystallographic, the space group would beI4122 with acaxis three times shorter and a single FBPase subunit in the asymmetric unit.I4122 is a minimal, non-isomorphic supergroup of the four primitive tetragonal space groups, explaining the space-group ambiguity for this crystal.