Solution structure and basis for functional activity of stromal cell‐derived factor‐1; dissociation of CXCR4 activation from binding and inhibition of HIV‐1
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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.
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The CCL11 protein product resulting from differential signal peptide cleavage is predicted to retain additional amino-acid residues at its N terminus, a key region specifying binding and activity of chemokines.
“The protein product of CCL11 resulting from differential signal peptide cleavage is predicted to retain additional amino-acid residues at its N terminus, a key region specifying binding and activity of chemokines.44”
From Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease (2015) · cites this paper as [44]
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- Authors
- Crump, M. P., Gong, J., Loetscher, P., Rajarathnam, K., Amara, A., Arenzana‐Seisdedos, F., Virelizier, J., Baggiolini, M., Sykes, B. D., & Clark‐Lewis, I.
- Affiliations
- University of Alberta (CA)
- University of British Columbia (CA)
- University of Bern (CH)
- Institut Pasteur (FR)
- Corresponding author
- Sykes, Brian D.
- Clark‐Lewis, Ian
- Venue
- The EMBO Journal
- Published
- 1997-12-01
- Volume
- 16
- Issue
- 23
- Pages
- 6996-7007
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1170303
- OpenAlex
- W1964083898
- Cited by
- 731
- References
- 45
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 19 · 2023: 14 · 2022: 17 · 2021: 15 · 2020: 29 · 2019: 32 · 2018: 20 · 2017: 35 · 2016: 26 · 2015: 34 · 2014: 30 · 2013: 44 · 2012: 35
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada
- Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- CXCL12, chemokine structure, N-terminal disordered region, receptor binding sites, CXCR4, HIV-1 coreceptor, HIV-1 entry inhibition, receptor activation, chemokine antagonists
- MeSH terms
- Amino Acid Sequence, Binding Sites, Models, Biological, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Conformation, Structure-Activity Relationship, Virus Replication, HIV-1, Sequence Homology, Amino Acid, Chemokines, Anti-HIV Agents, Receptors, CXCR4, Chemokines, CXC, Nuclear Magnetic Resonance, Biomolecular, Chemokine CXCL12
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