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- Title
Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1.
- Authors
Crump, Matthew P.; Jiang-Hong Gong; Loetscher, Pius; Rajarathnam, Krishna; Amara, Ali; Arenzana-Seisdedos, Fernando; Virelizier, Jean-Louis; Baggiolini, Marco; Sykes, Brian D.; Clark-Lewis, Ian
- Abstract
The three-dimensional structure of stromal cell-derived factor-1 (SDF-1) was determined by NMR spectroscopy. SDF-1 is a monomer with a disordered N-terminal region (residues 1–8), and differs from other chemokines in the packing of the hydrophobic core and surface charge distribution. Results with analogs showed that the N-terminal eight residues formed an important receptor binding site; however, only Lys-1 and Pro-2 were directly involved in receptor activation. Modification to Lys-1 and/or Pro-2 resulted in loss of activity, but generated potent SDF-1 antagonists. Residues 12–17 of the loop region, which we term the RFFESH motif, unlike the N-terminal region, were well defined in the SDF-1 structure. The RFFESH formed a receptor binding site, which we propose to be an important initial docking site of SDF-1 with its receptor. The ability of the SDF-1 analogs to block HIV-1 entry via CXCR4, which is a HIV-1 coreceptor for the virus in addition to being the receptor for SDF-1, correlated with their affinity for CXCR4. Activation of the receptor is not required for HIV-1 inhibition.
- Subjects
CHEMOKINES; G proteins; NUCLEAR magnetic resonance spectroscopy; PROTEIN synthesis; HIV; MONOMERS; BINDING sites
- Publication
EMBO Journal, 1997, Vol 16, Issue 23, p6996
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/16.23.6996