Crystal structure of phosphoglucomutase from Leishmania major at 3.5Å resolution.

Abstract

The crystal structure of phosphoglucomutase (LmPGM) from the parasite Leishmania major has been solved at 3.5Å resolution. Although the active form of the enzyme is monomeric in solution, four molecules (A, B, C, D) were found in the asymmetric unit, of which the pairs (A,D) and (B,C) were of identical inter-subunit geometry. The parasitic enzyme constituted of four domains exhibited the canonical 'heart' shape of the protein, with domains I to III having a conserved α|β core, while the fourth (IV) domain being structurally distinct from the rest. Conformational variability of the IVth domain, postulated to be responsible for the catalytic function of the enzyme has been studied by normal mode analysis (NMA) and the conformational features responsible for domain movement in the 'hinge region' analyzed in detail. Although the active site of phosphoglucomutase is highly conserved from parasite to human, initial calculations show that a ligand binding pocket could exist near the hinge region, which is unique to the parasite. The enzymatic parameters of LmPGM have been determined and compared with other PGMs from orthologous species in addition to elucidating its mechanism of action by docking the substrate, intermediate onto the active site.