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1.
FIGURE 1.

FIGURE 1. From: Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase.

The PBGS-catalyzed reaction. PBGS catalyzes the condensation of two molecules of ALA to form porphobilinogen and two water molecules. A-side ALA (thick lines) becomes the acetyl-containing half of porphobilinogen; P-side ALA (thin lines) becomes the propionyl-containing half.

Eileen K. Jaffe, et al. J Biol Chem. 2011 April 29;286(17):15298-15307.
2.
FIGURE 6.

FIGURE 6. From: Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase.

A comparison of PBGS active site structures. a, the TgPBGS active site is illustrated with heteroatoms colored cpk; the carbons of porphobilinogen are green; active site lid residues are labeled with an asterisk. b, the yeast PBGS active site (PDB code 10HL) is colored as in a with the carbons of the heterocyclic reaction intermediate colored dark yellow, and the active site zinc shown as a maroon sphere; active site lid residues are labeled with an asterisk.

Eileen K. Jaffe, et al. J Biol Chem. 2011 April 29;286(17):15298-15307.
3.
FIGURE 5.

FIGURE 5. From: Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase.

A comparison of the structure of PBGS from various species. Two images are provided to illustrate the considerable variation observed in the conformation of PBGS N and C termini. Structures are overlaid for a single subunit from TgPBGS (PDB code 3OBK, green), yeast PBGS (PDB code 1OHL, yellow), C. vibrioforme PBGS (PDB code 2CLH, cyan), and P. aeruginosa PBGS (PDB code 2WOQ, magenta). Where visible, the N and C termini of TgPBGS are labeled; cylindrical arrows are provided adjacent to one helix to facilitate orientation.

Eileen K. Jaffe, et al. J Biol Chem. 2011 April 29;286(17):15298-15307.
4.
FIGURE 2.

FIGURE 2. From: Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase.

The quaternary structure dynamic of some PBGS. Human PBGS crystal structures (PDB codes 1E51 and 1PV8) are used to illustrate the alternate assemblies the protein can adopt. The alternate dissociation pathways denote possible mechanisms for PBGS oligomer dissociation to dimers. The hugging and detached dimers (pathway A) are the asymmetric crystallographic units of the crystal structures. Based on the hydrophobicity and hydrophilicity of surfaces exposed upon dissociation, the pro-octamer and pro-hexamer dimers (pathway B) of human PBGS have been proposed to be the physiologically relevant dimers (4). The “twist” that describes the transition between the pro-octamer and pro-hexamer dimers is illustrated by the enlarged sections that denote ϕψ angles at residue 23 (asterisk).

Eileen K. Jaffe, et al. J Biol Chem. 2011 April 29;286(17):15298-15307.
5.
FIGURE 7.

FIGURE 7. From: Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase.

The allosteric magnesium ion-binding site. a, two allosteric magnesium ions (green spheres and red arrows) are shown at the intersection of two pro-octamer dimers (green-blue and yellow-gray). b, a crossed-eye stereo image illustrating the details of the allosteric magnesium binding site indicated by the larger red arrow in a. Carbons are colored according to their subunit (blue or yellow). Dark blue spheres are the first coordination sphere water molecules. Light blue spheres are additional water molecules. Also illustrated are the nearby intersubunit interactions between the active site lid of the yellow subunit and the N-terminal arm of the blue subunit.

Eileen K. Jaffe, et al. J Biol Chem. 2011 April 29;286(17):15298-15307.
6.
FIGURE 4.

FIGURE 4. From: Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase.

The TgPBGS structure. a, two orthogonal orientations of the TgPBGS octamer showing each subunit in a different color, with the subunits labeled A–H. On the left, all subunits are shown as spheres. On the right, subunits A, D, E, and G are shown as ribbons to illustrate the intersubunit location of each N-terminal arm (N temini are labeled where visible). b, using the same orientation and coloring as the right side of part a, three subunits (A, B, and C) are illustrated in ribbon representation. Porphobilinogen is shown as sticks in each active site, colored as the subunit. For each subunit, the N-terminal arm and the C-terminal tail are in a darker shade. The N-terminal arm of the magenta subunit wraps around the αβ-barrel domain of the gold subunit, constituting the hugging dimer (see Fig. 2). The N-terminal arm of the magenta subunit lies against the internal face of the αβ-barrel domain of the cyan subunit, constituting the pro-octamer dimer (see Fig. 2). The C-terminal tails of the pro-octamer dimer form an intersubunit β-sheet (tail swap), emphasized in c. c, using the same orientation as in part b, and pale colors for the rest of subunits A and C, the tail swap is highlighted (circled in black). d, details of the C-terminal tail portion of the pro-octamer dimer illustrate additional intersubunit interactions between the C-terminal β-strand of the magenta subunit and both the N-terminal arm and αβ-barrel region of the cyan subunit. Reciprocal interactions are not shown. e, the eight subunits of the TgPBGS crystallographic asymmetric unit are overlaid using wireframe representation and colored by thermal factors (red is hot or mobile, and blue is cold or fixed). Porphobilinogen at the active site is shown in spheres.

Eileen K. Jaffe, et al. J Biol Chem. 2011 April 29;286(17):15298-15307.
7.
FIGURE 3.

FIGURE 3. From: Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase.

Alignment of PBGS protein sequences highlighting key features essential for structure and function. This alignment omits hundreds of species of PBGS that do not contain the C-terminal extension. Amino acid numbering (residues 1–356) pertains to the TgPBGS construct used for the current crystal structure. Negative numbers correspond to the extended N-terminal that include low complexity region of TgPBGS, which is not included in the expression construct. N-terminal portions of Pisum sativum and Plasmodium falciparum PBGS are shown with negative numbering but not aligned with each other or TgPBGS. Alignment was done using the ClustalW2 program (43). Species abbreviations are as follows: Tgo, T. gondii; Pfa, P. falciparum; Psa, P. sativum (pea); Vch, V. cholerae; Pae, P. aeruginosa; Cvi, C. vibrioforme; Eco, E. coli; Sce, yeast; Hsa, human. The underlined species are ones for which there is a crystal structure, including T. gondii (this work). The extended N and C termini of TgPBGS are shown in blue. The cysteine-rich region that binds an active site zinc ion is in red, and the cysteines that coordinate zinc are highlighted in yellow. PBGS that do not use an active site zinc lack the cysteine residues but contain aspartic acid residues (highlighted in gray), which were proposed to coordinate magnesium (34). The residues involved in allosteric magnesium ion coordination are highlighted in red. The active site lid residues are green. Conserved active site residues are highlighted in purple. The asterisk denotes amino acid positions, which contain identical residues (shown in boldface) in all proteins aligned here.

Eileen K. Jaffe, et al. J Biol Chem. 2011 April 29;286(17):15298-15307.

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