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. 2021 Nov 22;12:6783. doi: 10.1038/s41467-021-27032-x

Fig. 1. The human MLKL pseudokinase domain and RIPK3 kinase domain form a face-to-face complex.

Fig. 1

a Orthogonal views of the co-crystal structure of human RIPK3 (residues 1–316; C3S, C110A):human MLKL (residues 190–471). MLKL (gray), αC helix (yellow), and activation loop (green) are highlighted. RIPK3 (wheat), αC helix (pink), and activation loop (cyan) are highlighted. Compound 10 (magenta) and key phosphorylation sites (RIPK3:pS227, pT224; MLKL:T357, S358), and F386 are shown as sticks. Dashed lines represent chain connectivity where insufficient electron density was observed to allow model building. b Zoomed view of Compound 10 binding to the human RIPK3 active site. Sidechains and backbone atoms interacting with Compound 10 (magenta) are shown as sticks. Electrostatic interactions are shown as black dashed lines. Transparent surfaces are shown for residues that hydrophobically interact with Compound 10. c Overlay of human RIPK3 (gray):MLKL (wheat) (this study; PDB: 7MON) with the mouse RIPK3 (green):MLKL (blue) complex (PDB: 4M69)46. Alignment was performed by superimposing the respective MLKL in each complex model using UCSF Chimera Matchmaker. d Zoomed view of the C-lobe electrostatic and hydrophobic interactions within the human RIPK3:MLKL structure. Sidechains involved in electrostatic interactions are shown as sticks; sidechains mediating non-polar interactions are shown as thin lines. Electrostatic interactions are shown with red dashed lines or in blue when hidden behind sidechains. e Zoomed views of the C-lobe electrostatic interactions from the mouse RIPK3:MLKL structure. Peptide backbones are shown as silhouettes. Sidechains involved in electrostatic interactions are shown as sticks and labeled. Electrostatic interactions are shown with red dashed lines or in blue when hidden behind sidechains. Dashed red semi-circles illustrate the potential electrostatic repulsion between mouse MLKL K405 and RIPK3 R241. Electrostatic interactions from the human RIPK3:MLKL structure are overlaid (thin black dashed lines) with human residue sidechains shown as thin transparent sticks.