Journal:Acta Cryst F:S2053230X20011309

Multiple crystal forms of human MacroD2

Sarah Wazir, Mirko M. Maksimainen and Lari Lehtiö ^[1]

Molecular Tour
MacroD2 is one of the three human macrodomain proteins characterized for their protein linked mono-ADP-ribosyl-hydrolyzing activity. MacroD2 is a single domain protein containing a deep ADP-ribose binding groove. In this study new crystallization conditions for MacroD2 were found and three crystal structures of human MacroD2 in apo state were solved in space groups P4₁2₁2, P4₃2₁2 and P4₃ and refined at 1.75, 1.90 and 1.70 Å resolutions, respectively. Structural comparison of the apo crystal structures to the previously reported MacroD2 crystal structure in complex with ADP-ribose revealed conformational changes in the side chains of Val101, Ile189 and Phe224 induced by the binding of ADP-ribose into the active site. These conformational variations may potentially facilitate design efforts of a MacroD2 inhibitor.

Ribbon representations of the secondary structures of apo MacroD2 in:

• (PDB ID 6y4y, chain A) (light blue).
• (PDB ID 6y4z, chain A) (warm pink).
• (PDB ID 6y73, chain A) (salmon).

. Secondary structures of P4₁2₁2 (PDB ID 6y4y), P4₃2₁2 (PDB ID 6y4z), and P4₃ (PDB ID 6y73) are coloured as light blue, warm pink and salmon, respectively.

: MacroD2-ADPr complex structure (PDB ID 4iqy; (orange) and ligand-free MacroD2 (PDB ID 6y4y) (light blue). ADPr and its surrounding residues are shown as sticks. The labelled residues are important for the catalytic activity of the enzyme. The hydrogen bonds are presented as dash lines. Wa is the catalytic water molecule in MacroD2-ADPr complex.

Crystal structure comparison of MacroD2 (PDB ID 6y4y) and MacroD1 (PDB ID 2x47) catalytic fragments showing their mono-ADP-ribosyl-hydrolase functions:

• . MacroD2 structure (light blue), ligand-free MacroD1 (cyan). The ADPr of the MacroD2-ADPr structure is coloured in orange (PDB ID 4iqy).
• . ADPr and its surrounding residues are shown as sticks. The labelled residues are important for the catalytic activities of these enzymes.

References

1. ↑ Wazir S, Maksimainen MM, Lehtio L. Multiple crystal forms of human MacroD2. Acta Crystallogr F Struct Biol Commun. 2020 Oct 1;76(Pt 10):477-482. doi:, 10.1107/S2053230X20011309. Epub 2020 Sep 15. PMID:33006575 doi:http://dx.doi.org/10.1107/S2053230X20011309