A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5 - PubMed (original) (raw)

Figure 4

Structural model of the TM domain of the CCR5 receptor. TM helical segments, labeled 1–7, are shown as cyan-colored ribbons. The amino acid residues substituted by alanine are shown with space-filling atoms and are color-coded as follows: alanine substitutions of red-colored residues had a strong inhibitory effect on the antiviral activity of TAK-779 (Leu33, Tyr37, Trp86, Tyr108, Thr123); alanine substitutions of orange-colored residues had an intermediate effect (Arg31, Thr82, Ile198, Glu283); alanine substitutions of yellow-colored residues had a borderline effect (Phe79, Leu104); alanine substitutions of dark blue-colored residues had no effect (Phe41, Asn48, Ile52, Leu55, Ile56, Leu69, Asn71, Asp76, Thr105, Phe112, Phe113, Phe117, Phe118, Leu121, Leu122, Phe144, Thr195, Leu255, Asn258, Thr259, Met279, His289, Tyr297). Light blue-colored residues indicate mutations that caused poor expression of CCR5 (Tyr68, Phe85, Tyr251, Asn252, Asn293). These receptors could not be evaluated for HIV-1 entry. (A) View of CCR5 from within the plane of the membrane. The extracellular surface is toward the top of the figure, the cytoplasmic surface toward the bottom. For orientation, Arg31 is at the upper left in orange, and Phe144 is at the lower right in blue. (B) View of CCR5 from its extracellular surface. The model is rotated by approximately 90° from the orientation in A.