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. 2017 Oct 17;6:e28020. doi: 10.7554/eLife.28020

Figure 3. X-ray crystal structure analysis of GRL-142 with HIV-1 protease.

Figure 3.

(A) X-ray crystal structure of wild-type HIV-1 protease (PRWT) in complex with DRV or GRL-142. The crystal structure of GRL-142 in complex PRWT was solved (PDB ID: 5TYS). The polar interactions of GRL-142 with protease residues in the active site are shown, and the interactions of DRV with PRWT (PDB ID: 4HLA) are shown for comparison. Cross-section of protease backbone is shown in green and red ribbons. The carbon atoms of GRL-142 and DRV are shown in off-white and green respectively. Nitrogen, oxygen, sulfur, fluorine, and hydrogen atoms are shown in blue, red, yellow, cyan, and white, respectively. Hydrogen bond interactions are shown by yellow dashed lines and polar interactions from fluorine are shown by cyan dashed lines. (B) Focus on the P2 and P2´ site interactions of DRV vs GRL-142. On the top panel, side by side comparison of bis-THF group of DRV (left panel) with crn-THF group of GRL-142 (right panel) in complex with HIV-1 protease. The crn-THF is larger with two two extra carbon atoms that contribute additional van der Walls interactions, particularly with three residues, I47, V32 and L76 in close proximity. On the lower panel, benzothioazole moiety of GRL-142 (right panel) with formation of extra ring effectively fills up the S2´subpocket. While sulfur atom forms close contact with I47’, cyclopropyl moiety protrudes outside the binding pocket and forms close contact with K45´. (C) Zoomed-in feature of the fluorine-mediated interactions inside the S1 pocket of dimerized PRWT. The distances between the fluorine atoms and the interacting atoms less than 3.2 Å are shown as dashed cyan lines. While one fluorine of the bis-meta-fluorophenyl group is heavily involved in halogen bonding with G49, I50 and P81’, the other fluorine atom forms halogen bonds with the positively charged guanidinium group of R8’ as well as the side chain of V82’. The right panel scheme shows the halogen bonding within the S1 pocket as highlighted in light orange crescent shade. (D) GRL-142 has greater vdW contacts with I32 than with V32. The vdW interactions of GRL-142 with V32 and V32' (green surfaces) in PRWT and with I32 and I32' (red surfaces) in PRV32I mutant protease are shown. GRL-142 is shown in grey surface.