Figure 1.
Primate lentiviral intasome structures and INSTI binding. (A) Chemical structures of licensed second-generation INSTIs BIC and DTG highlight heteroatoms that interact with IN active site metal ions (red arrows) as well as divergent A-rings and halobenzyl groups. (B) SIVrcm (green; Protein Data Base [PDB] code 6RWL) and HIV-1 (cyan; PDB code 6PUT) intasomes were superimposed via Cα positions of active site residues Asp64, Asp116, and Glu152 (respective side chains shown as sticks). Residues that when changed confer INSTI resistance and terminal CA nucleotides of the vDNA plus-strand as well as the dG of the opposing strand that pairs with dC are also shown as sticks; position 138 is Glu in HIV-1 IN and Thr in SIVrcm IN. Red and blue, oxygen and nitrogen, respectively. Cyan spheres, calcium atoms in the HIV-1 model. Local resolutions of the active site regions of the SIVrcm and HIV-1 intasomes reached 2.8 Å and 2.7 Å, respectively. (C) Superposition of BIC-bound SIVrcm (PDB code 6RWM) and HIV-1 (PDB code 6PUW) intasomes, oriented as in panel B. Displaced 3′-dAOH nucleotides were omitted for clarity. Green and cyan spheres, magnesium ions in respective SIVrcm and HIV-1 structures; white, fluorine atoms of INSTI halobenzyl groups. Other labeling same as in panel B; local resolutions of these SIVrcm and HIV-1 active site regions were 2.4 Å and 2.7 Å, respectively. PyMOL [40] was used to generate panel B and C structures.