Figure 3.

Human GBA2 structural model. (A) Overall structure of the human GBA2 model (purple) superimposed with the TxGH116 structure (green). The loop adjacent to the active site, which is longer in GBA2, is marked with a red arrow, while the longer loop between helices H5 and H6 of the (α/α)₆ solenoid domain is marked with a black arrow. (B) Diagram of human GBA2 model showing positions of residues mutated in human disease (space-filling) and interacting residues and ligand (sticks). (C) Superposition of active site residues of human GBA2 and the TxGH116 complex with glucose. All of the sugar binding residues are conserved between TxGH116 and GBA2, as well as the aspartate (D508) that interacts with H507 in TxGH116. The H-bonds between residues involved in human autosomal recessive cerebellar ataxia mutations and the sugar residue are shown as dashed lines. The catalytic nucleophile and acid/base labels are underlined. (D) Superposition of human GBA2 model (purple) on TxGH116 structure (green) in the area of the R630 residue mutated in certain hereditary spastic paraplegia cases. R630 and the nearby carboxylate residues D631 and E555 are conserved with TxGH116 residues. (E) View of GBA2 F419 and the conserved interacting aromatic groups in the overlay of the GBA2 and TxGH116 models. (F) Position of the GBA2 G683R mutation, showing that, although it is near the surface of the protein, G683 is tightly opposed to S741 (both shown in magenta spheres) and the bound calcium cation (green sphere) and is also linked to the catalytic acid/base D677 shown next to the glucosyl residue (cyan carbon sticks).