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. 2021 Jul 27;4:916. doi: 10.1038/s42003-021-02387-5

Fig. 4. NMR solution structure of ApoL1-NTD at pH 5.5 reveals different conformational state of helix 5.

Fig. 4

a Ribbon diagram of the 20 lowest energy ApoL1-NTD structures in rainbow colors (colored from blue to red (N- to C-term) according to colors of increasing wavelength). b Overlay of the lowest energy state from the NMR-calculated ensemble of ApoL1-NTD structures depicted in a (orange) with ApoL1-NTD from the Fab6D12 crystal structure (dark green). Both structures share the four-helix core conformation, but the NMR structure differs by having a disordered linker region (helix 4–5 linker) that ends with a well-structured helix 5 (BH3-like region in cyan), which packs against the four-helix core. In this structure, only the Fab6D12 epitope is formed, but not that of Fab7D6 or Fab3B6. c Overlay of the lowest energy state from the NMR-calculated ensemble of ApoL1-NTD structures depicted in a (orange) with ApoL1-NTD from the Fab3B6 crystal structure (chain C; blue with epitope residues in yellow). In contrast to the NMR structure (helix 5 in the “bound state”), the crystal structure shows that helix 5 (ending with the BH3-like helix; pink color) projects away from the four-helix core; in this structure, all three antibody epitopes are formed and are accessible. d Model of the two conformational states of helix 5. The “bound state” (NMR structure) in which helix 5 (orange with C-terminal BH3-like region in blue) is placed in a groove formed by helices 1 and 2 is in equilibrium with the “open state” (Fab3B6 structure) in which the helix 5 projects away from the four-helix core and is elongated due to the addition of linker residues into the helix. The vacated groove in the “open state” could be occupied by other interactors, such as the C-terminal Leu zipper helix (“Leu zipper” as cylinder) of ApoL family members. e. Surface representation of the four-helix core (surface is colored according to approximate net electrostatic potential: blue, positive; red, negative) with helix 5 (cyan) and the helix 4–5 linker (blue) as cartoon. The shallow groove that harbors helix 5 (mainly its BH3-like portion) is composed of a hydrophobic and a negatively charged portion. The main hydrophobic contacts are made by helix 5 residues L151, I155, and L158 forming the LxxxIxxL motif (cyan sticks; underlined residues), whereas K148, R156, and R159 engage with the acidic portion (cyan sticks).