Pepducins are lipopeptide antagonists of CXCR4 in human leukemia and lymphoma cell lines. (A) A model of the 3-dimensional structure of CXCR4 based on the structure of rhodopsin demonstrates the topological arrangement of the intracellular loops. G proteins are recruited to the intracellular loops of CXCR4 and mediate downstream signaling in response to ligand binding. (B) Schematic representation of CXCR4 with i1 and i3 loop amino acid sequences. (C) Sequences of the CXCR4 pepducins and control peptides. Pepducins with N-terminal palmitate (Pal) based on the sequence of the i1 (PZ-218 and PZ-217) and i3 (PZ-210) intracellular loops. Control peptides lacking an N-terminal palmitate moiety and corresponding to the i1 (PZ-253) and i3 (PZ-254) loop sequences were synthesized. (D) Effect of CXCR4 pepducins on human hematopoietic cell calcium flux. Cells were preincubated with vehicle or the indicated pepducins and stimulated with CXCL12.