Crystal structure of chemically synthesized [N33A] stromal cell-derived factor 1α, a potent ligand for the HIV-1 "fusin" coreceptor

Stromal cell-derived factor-1 alpha (SDF-1 alpha) is a member of the chemokine superfamily and functions as a growth factor and chemoattractant through activation of CXCR4/LESTR/Fusin, a G protein-coupled receptor. This receptor also functions as a coreceptor for T-tropic syncytium-inducing strains of HIV-1, SDF-1 alpha antagonizes infectivity of these strains by competing with gp120 for binding to the receptor. The crystal structure of a variant SDF-1 alpha ([N33A]SDF-1 alpha) prepared by total chemical synthesis has been refined to 2,2-Angstrom resolution. Although SDF-1 alpha adopts a typical chemokine beta-beta-beta-alpha topology, the packing of the alpha-helix against the beta-sheet is strikingly different. Comparison of SDF-1 alpha with other chemokine structures confirms the hypothesis that SDF-1 alpha map be either an ancestral protein from which all other chemokines evolved or the chemokine that is the least divergent from a primordial chemokine, The structure of SDF-1 alpha reveals a positively charged surface ideal for binding to the negatively charged extracellular loops of the CXCR-4 HIV-1 coreceptor, This ionic complementarity is likely to promote the interaction of the mobile N-terminal segment of SDF-1 alpha with interhelical sites of the receptor, resulting in a biological response.