Extended Data Fig. 10: Structural details of the interaction between MA and SP2 and comparison with other side pocket ligands.
From: The conserved HIV-1 spacer peptide 2 triggers matrix lattice maturation
a, Atomic model of the dimeric interface of the mature MA lattice, with bound SP2, viewed from outside the virus (MA; Blue, SP2; orange). b, Rotated and zoomed in view of SP2 within the MA binding pocket from the side. c, Zoomed in view of (a). The C terminus of two adjacent SP2 chains and R22 from the two opposing MA molecules form a favourable electrostatic interaction network across the symmetry axis. This interaction likely results in the favouring of the mature MA lattice configuration upon SP2 binding to MA. d-f, Zoomed in views of b. d, Central SP2 binding motif residues P13, G14 and N15 sit in a hydrophobic cleft in the MA side pocket, formed by residues in helices 2, 4 and 5 as well as in the α-helix 1-2 loop. e, Binding of SP2 R12 is supported by a hydrophobic contact with W36 and an electrostatic interaction with residues E73 and E74. f, Binding of SP2 F16 is facilitated by a hydrophobic contact with R76. g, MA bound to SP2 (left. MA: pink, SP2: orange): R22 in the α-helix 1-2 loop forms an electrostatic interaction with the C-terminal carboxyl group of SP2, whereas K27 does not interact with SP2 (left). MA bound to PtdIns(4,5)P212 (middle. MA green; PI(4,5)P2 orange): R22 and K27 interact with the PtdIns(4,5)P2 4′-phosphate and bridging 1′-phosphodiester respectively. MA bound to tRNA (right. MA purple; tRNALys3 orange): R22 forms an interaction with a 2′-OH ribose moiety (tA57) and a 4 O ribose position on the tRNA backbone (tU20) whereas K27 interacts with a backbone phosphate group (tA58) (right)23. h, Left: α-Helix 2 residues, H33 and W36, form π-stacking interactions with P11 and the R12 backbone amide of SP2 respectively. K32 does not interact with SP2. Middle: H33 forms an electrostatic interaction with the 1′ phosphate of PI(4,5)P2. Right: Both K32 and H33 form electrostatic interactions with backbone phosphate of the tRNA (tA57), whereas W36 forms a π stacking interaction with tC56. i, Left: α-Helix 4 residue E73 forms a salt bridge with R12 of SP2. F16 of SP2 packs against the acyl tail of R76. Middle: R76 forms an electrostatic interaction with the 5′-phosphate of PI(4,5)P2. Right: R76 interacts with a backbone phosphate of tRNA as well as a ribose 2′-OH (tG16).
