Figure 1.
2D structures of (A) dolutegravir, (B) raltegravir and (C) elvitegravir.
Red ovals encircle the oxygen atoms that chelate the divalent metal cations in the active site; green ovals encircle the halobenzyl groups; and blue boxes encircle the approximate regions of the scaffolds that can accommodate positive charge after chelation of the metals. The purple circles at (B) encircle raltegravir’s gem-dimethyl (small circle) and oxadiazole groups, and the purple oval at (C) encircles elvitegravir’s 1-hydroxymethyl-2-methylpropyl group.
Figure 2.
Structural models of HIV-1 integrase with U5 LTR DNA and (A, B) raltegravir, (C) elvitegravir or (D) dolutegravir.
For raltegravir, the terminal 3′ adenylate is depicted in 2 distinct conformations: panel 2A shows the published conformer and panel 2B shows an alternative conformer that is also consistent with the observed electron density. Raltegravir, elvitegravir and dolutegravir are in stick representation with carbon, nitrogen, oxygen, fluorine and chlorine atoms colored gray, blue, red, cyan and green, respectively. A select subset of amino acids and nucleotides is depicted and labeled with residue type and number (numbering schemes as listed in Figure S1); all residues are in stick representation with carbon atoms colored by secondary structure/chain and nitrogen and oxygen atoms colored blue and red, respectively. The Mg2+ ions are represented as small yellow spheres with coordinate bonds to the inhibitors depicted as dashed yellow lines.
Figure 3.
Structural model of Q148R HIV-1 integrase with U5 LTR DNA.
The side chain of residue Q148R was modeled interacting with the side chain of E152 and in this conformation the residue may interfere with the binding of elvitegravir. Molecular representations and coloring schemes as described in Figure 2.
Figure 4.
Structural models of (A) Q148H/G140S and (B) N155H HIV-1 integrase with U5 LTR DNA and dolutegravir.
(A) The Q148H/G140S mutations are predicted to disrupt the structure of the flexible active-site loop, displacing the 310 helix away from the DDE motif and weakening the H-bond interaction between the backbone CO of Q148H and the backbone NH of E152. (B) The N155H mutation is predicted to disrupt the structure of the α4 helix, widen the base of the catalytic pocket, alter the placement of at least the Mg2+ ion coordinated to residues D64 and E152 and alter the conformation of the terminal 3′ adenosine forming part of the pocket. Molecular representations and coloring schemes are described in Figure 2.