Crystal structure of chemically synthesized [N33A] stromal cell-derived factor 1alpha, a potent ligand for the HIV-1 "fusin" coreceptor.
Stromal cell-derived factor-1alpha (SDF-1alpha ) 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-1alpha antagonizes infectivity of these strains by competing with gp120 for binding to the receptor. The crystal structure of a variant SDF-1alpha ([N33A]SDF-1alpha ) prepared by total chemical synthesis has been refined to 2.2-A resolution. Although SDF-1alpha 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-1alpha with other chemokine structures confirms the hypothesis that SDF-1alpha may 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-1alpha reveals a positively charged surface ideal for binding to the negatively charged extracellular loops of the CXCR4 HIV-1 coreceptor. This ionic complementarity is likely to promote the interaction of the mobile N-terminal segment of SDF-1alpha with interhelical sites of the receptor, resulting in a biological response.
Dealwis
C
C
Department of Pharmacology, Yale University School of Medicine, New Haven CT 06510, USA.
Fernandez
E J
EJ
Thompson
D A
DA
Simon
R J
RJ
Siani
M A
MA
Lolis
E
E
D001665:Binding Sites; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000819:agonists* / Q000276:immunology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D008024:Ligands; D019718:Receptors, CXCR4