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. 2022 Jul 8;50(13):7545–7559. doi: 10.1093/nar/gkac573

Figure 4.

Figure 4.

Conformational flexibility of the C-terminal domain. (A) Plot of relative fluctuations by residue determined by coarse grained normal mode analysis on an isolated monomer from a tetrameric SAMHD1 structure (PDB: 6TXC) (black) and by alignment of isolated monomers from tetrameric structures of SAMHD1 T592V (PDB: 4ZWE) and SAMHD1 T592E (PDB: 4ZWG) (pink). Secondary structure is indicated at the top of the plot, with black bars indicating α-helices, and red bars indicating β-sheets. The C-terminal Domain (CtD) and flexible hinge region are labeled above the plot. (B) Fluctuations determined by normal mode analysis mapped on the structure of SAMHD1 (PDB: 6TXC). (C) Deformation energy determined by normal mode analysis mapped on the structure of SAMHD1 (PDB ID 6TXC). (D) Conformations of the C-terminal domain (CtD) (T592V – PDB: 4ZWE, T592E – PDB: 4ZWG). The T592E mutation causes the CtD to shift away from the allosteric sites and towards the active site. (E) Local resolution cryo-EM map of full-length hSAMHD1 bound to dGTPαS. The cryo-EM map is shown at a lower contour to highlight the lower resolution (blue) SAM and C-terminal domains. (F) An atomic model based on the SAMHD1 catalytic domain was docked into (E), showing the residual unmodeled densities corresponding to the SAM domains.