The Conformation and Orientation of a 27-Residue CCR5 Peptide in a Ternary Complex with HIV-1 gp120 and a CD4-Mimic Peptide

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• 作者：Einat Schnur¹ ; Eran Noah¹ ; Inbal Ayzenshtat¹ ; ¹ ; Hasmik Sargsyan² ; Tatsuya Inui² ; Fa-Xiang Ding² ; Boris Arshava² ; Yael Sagi¹ ; ¹ ; Naama Kessler¹ ; Rina Levy¹ ; Tali Scherf³ ; Fred Naider² ; Jacob Anglister¹ ; ^{Jacob.Anglister@weizmann.ac.il"" rel=""nofollow}
• 关键词：sulfotyrosine ; chemokine ; NMR ; protein structure ; interactions
• 刊名：Journal of Molecular Biology
• 出版年：2011
• 出版时间：29 July 2011
• 年：2011
• 卷：410
• 期：5
• 页码：778-797
• 全文大小：1389 K

文摘

Interaction of CC chemokine receptor 5 (CCR5) with the human immunodeficiency virus type 1 (HIV-1) gp120/CD4 complex involves its amino-terminal domain (Nt-CCR5) and requires sulfation of two to four tyrosine residues in Nt-CCR5. The conformation of a 27-residue Nt-CCR5 peptide, sulfated at Y10 and Y14, was studied both in its free form and in a ternary complex with deglycosylated gp120 and a CD4-mimic peptide. NMR experiments revealed a helical conformation at the center of Nt-CCR5(1–27), which is induced upon gp120 binding, as well as a helical propensity for the free peptide. A well-defined structure for the bound peptide was determined for residues 7–23, increasing by 2-fold the length of Nt-CCR5's known structure. Two-dimensional saturation transfer experiments and measurement of relaxation times highlighted Nt-CCR5 residues Y3, V5, P8–T16, E18, I23 and possibly D2 as the main binding determinant. A calculated docking model for Nt-CCR5(1–27) suggests that residues 2–22 of Nt-CCR5 interact with the bases of V3 and C4, while the C-terminal segment of Nt-CCR5(1–27) points toward the target cell membrane, reflecting an Nt-CCR5 orientation that differs by 180° from that of a previous model. A gp120 site that could accommodate ^CCR5Y3 in a sulfated form has been identified. The present model attributes a structural basis for binding interactions to all gp120 residues previously implicated in Nt-CCR5 binding. Moreover, the strong interaction of sulfated ^CCR5Tyr14 with ^gp120Arg440 revealed by the model and the previously found correlation between E322 and R440 mutations shed light on the role of these residues in HIV-1 phenotype conversion, furthering our understanding of CCR5 recognition by HIV-1.