Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1

Matthew P. Crump, Jiang Hong Gong, Pius Loetscher, Krishna Rajarathnam, Ali Amara, Fernando Arenzana-Seisdedos, Jean Louis Virelizier, Marco Baggiolini, Brian D. Sykes, Ian Clark-Lewis

Research output: Contribution to journalArticle

569 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6996-7007
Number of pages12
JournalEMBO Journal
Volume16
Issue number23
StatePublished - Dec 1 1997
Externally publishedYes

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Chemokine CXCL12
HIV-1
Chemical activation
Binding Sites
Charge distribution
Surface charge
Viruses
Chemokines
Nuclear magnetic resonance spectroscopy
Magnetic Resonance Spectroscopy
Monomers

Keywords

  • Chemokines
  • G-protein coupled receptors
  • Nuclear magnetic resonance spectroscopy
  • Protein synthesis
  • Stromal cell-derived factor-1

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Crump, M. P., Gong, J. H., Loetscher, P., Rajarathnam, K., Amara, A., Arenzana-Seisdedos, F., ... Clark-Lewis, I. (1997). Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO Journal, 16(23), 6996-7007.

Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. / Crump, Matthew P.; Gong, Jiang Hong; Loetscher, Pius; Rajarathnam, Krishna; Amara, Ali; Arenzana-Seisdedos, Fernando; Virelizier, Jean Louis; Baggiolini, Marco; Sykes, Brian D.; Clark-Lewis, Ian.

In: EMBO Journal, Vol. 16, No. 23, 01.12.1997, p. 6996-7007.

Research output: Contribution to journalArticle

Crump, MP, Gong, JH, Loetscher, P, Rajarathnam, K, Amara, A, Arenzana-Seisdedos, F, Virelizier, JL, Baggiolini, M, Sykes, BD & Clark-Lewis, I 1997, 'Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1', EMBO Journal, vol. 16, no. 23, pp. 6996-7007.
Crump, Matthew P. ; Gong, Jiang Hong ; Loetscher, Pius ; Rajarathnam, Krishna ; Amara, Ali ; Arenzana-Seisdedos, Fernando ; Virelizier, Jean Louis ; Baggiolini, Marco ; Sykes, Brian D. ; Clark-Lewis, Ian. / Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. In: EMBO Journal. 1997 ; Vol. 16, No. 23. pp. 6996-7007.
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