Fig. 2. AtHMG1 active site adopts a unique conformation.

a Apo AtHMG1 displays a single monomer in the asymmetric unit (dark-blue cartoon) which through crystallographic symmetry forms a homotetrameric assembly (ribbon) consisting of two canonical class I homodimeric HMGR folds (blue and green). b Overlay of human HMGR (orange cartoon, PDB 1HWK) with apo AtHMG1 (a) illustrates their conserved fold. c AtHMG1 (blue ribbon and sticks) has a highly conserved active site with HsHMGCR (orange ribbon and sticks). Active site-delineating residues are shown as sticks. All residues are conserved except the two AtHMGR1 residues labelled. d Superposition of atorvastatin in the active site of AtHMG1 illustrates the position of these substitutions relative to a bound statin. Conserved active site residues are shown with yellow surface and substitutions highlighted with magenta surface. e Conformational flexibility in the Nα4-Lβ1 loop of AtHMG1 (cyan dotted line) evidenced by poor electron density is likely the result of a Pro to Val substitution. This results in the loss of a type II hydrogen bonded β-turn exhibited in HsHMGCR (f) that allows HsHMGCR E559 to hydrogen bond (dashed grey lines) to the open lactone ring of statins. Atorvastatin superimposed on apo AtHMG1 (e, g) illustrates the equivalent residue, E265, likely too far away to H-bond to statins. Conserved active site residues (e–g) are shown with yellow surface. h Overlay of apo AtHMG1 (blue cartoon and sticks) with all published structures of HMGR (grey cartoon and sticks)^{24,26,30,40–50}. To the best of our knowledge, this conformation has not been seen in any published HMGR crystal structure to date. Topology designation from HsHMGCR⁴⁹.