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Figure 4
PAD6 structural analysis of the C-terminal domain. (a) Sequence alignment between five human PADs, focusing on the PAD6 loop I661–A678. Within this loop, the active or putative active cysteines are underlined and labelled: blue for PAD6, red for the other PADs. (b) Superimposition between structures of PAD6 and PAD4 in complex with substrate (PDB entry 2dew). The substrate is in yellow stick representation. (c) Same superimposition as in (b), showing a close-up view of the segment containing the I661–A678 loop and the β-strands connected by this loop, with the equivalent segment in PAD4 and the substrate. This view shows that the conformation of the PAD6 I661–A678 loop (blue) is different from the equivalent loop in PAD4 (I630–T647, red), and occludes the active site, so that the substrate would clash if positioned as in PAD4 (right panels). (d) PAD6 I661–A678 loop in blue superimposed with the equivalent segment of the apo PAD2 structure in green (PDB entry 4n20) and the inactive Ca2+-PAD3 in cyan (PDB entry 7d8n). Flexible loop I631–T648 (PAD3) represented by a dashed line. (e) Similarities in the active sites of the PAD6 structures and the apo PAD2 and non-productive form of Ca2+-bound PAD3, showing that equivalent Arg residues (Arg355 in PAD6, Arg347 in PAD2 and Arg346 in PAD3) occupy the active site, in lieu of the substrate. Ca2+ binding triggers the displacement of Arg347 in holo PAD2 (PDB entry 4n2c) together with other residues to shape a functional active site (right panel).

IUCrJ
Volume 11| Part 3| May 2024| Pages 395-404
ISSN: 2052-2525
https://doi.org/10.1107/S2052252524002549