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Figure 4.
Binding mode and interaction map of TMC353121 and effect of
the D486N mutation on the interactions. Binding mode of
TMC353121 in the complete 6HB (A). The RSV 6HB is composed of
three central HR1 helices (green surface) surrounded by three
antiparallel HR2 helices (blue surface). The 6HB axis is tilted
approximately 45 degrees from the plane of the page.
Superimposition of the TMC353121 cocrystal structure with the
1G2C RSV 6HB crystal structure (B). The HR1 and HR2 helices of
the cocrystal structure are dark green and blue, respectively,
and the HR1 and HR2 helices from the 1G2C 6HB structure are
shown in salmon and lilac, respectively. Displacement of
sidechains by TMC353121 is indicated by orange arrows.
Interaction map of TMC353121 with its 6HB target site (C).
H-bonds are drawn as black dotted lines. Distances (Å)
between interacting atoms are in black. TMC353121 makes a
π–π stacking interaction with Y198. Residues from two
neighboring HR1 or HR1’ and HR2 helices are indicated in green
and blue, respectively. Effect of the HR2 resistance mutation
D486N on electrostatic interactions in the TMC353121-bound 6HB
complex (D). HR1 or HR1’ and HR2 residues are indicated in
dark green and blue, respectively, and the calculated protein
surface of HR1 and HR2 in transparent green and blue,
respectively. HR2 residue 486 that causes resistance against
TMC353121 upon mutation is shown in red. Orange arrows indicate
hydrogen bonds. TMC353121 is colored by atom type (carbon =
gray; oxygen = red; nitrogen = blue).
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