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Solution structure and basis for functional activity of stromal cell‐derived factor‐1; dissociation of CXCR4 activation from binding and inhibition of HIV‐1
Open accessAbstract
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 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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BackgroundInfluentialStructural and Functional Basis of CXCL12 (Stromal Cell-derived Factor-1α) Binding to Heparin
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BackgroundMethodInfluentialStructural Basis for Coreceptor Selectivity by The HIV Type 1 V3 Loop
Cardozo, T. J., Kimura, T., Philpott, S. M., Weiser, B., Burger, H., & Zolla‐Pazner, S. (2007) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2006.0130 · Cited by 168
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The biochemistry and biology of the atypical chemokine receptors
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“Based on the fast and efficient binding process of the small molecule SDF-1a (8 kDa, w5 nm) [37] steric restrictions of the conjugation by the polymer network (see Table 1, mesh size 6.”
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Self-citationStructural Basis of Chemokine Receptor Function—A Model for Binding Affinity and Ligand Selectivity
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“Mutagenesis and the chimera data for other chemokines also indicate that the site-I and site-II interactions differentially influence binding affinity, selectivity, and activation [22, 34, 53, 68].”
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The CXCR3 Binding Chemokine IP-10/CXCL10: Structure and Receptor Interactions
Booth, V. K., Keizer, D. W., Kamphuis, M. B., Clark‐Lewis, I., & Sykes, B. D. (2002) · Biochemistry · doi:10.1021/bi026020q · Cited by 142
Self-citationDifferential regulation of CXCR4 and CCR5 endocytosis
Signoret, N. Y. M., ROSENKILDE, M. M., Klasse, P. J., Schwartz, T. W., Malim, M. H., Hoxie, J. A., & Marsh, M. (1998) · Journal of Cell Science · doi:10.1242/jcs.111.18.2819 · Cited by 142
Metal Ion Enhanced Binding of AMD3100 to Asp262 in the CXCR4 Receptor
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The sweet spot: how GAGs help chemokines guide migrating cells
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“Early studies on CXCL8 [27] and CXCL12 [28] demonstrated that chemokine binding to, and activation of, their corresponding receptors occur independently and rely on 2 distinct domains.”
BackgroundSelf-citationSignal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices
Wescott, M. P., Kufareva, I., Paes, C., Goodman, J. R., Thaker, Y., Puffer, B. A., Berdougo, E., Rucker, J. B., Handel, T. M., & Doranz, B. J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1601278113 · Cited by 140
“In the CXCR4:CXCL12 complex model, each of these four residues directly contacts or is in close proximity to the distal N terminus of CXCL12 (residues K1 and P2), which is widely recognized as the critical domain of the chemokine that initiates signaling (16, 26).”
BackgroundFunctional diversity of SDF-1 splicing variants
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“CXCR4 and SDF-1 genes are remarkably conserved across diverse species, suggesting their key biological significance in development [62,63].”
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New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model
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“Subsequent studies expanded the importance of this region for site 1 interactions to other CC and CXC chemokines, establishing the N-loop as a critical motif for CKR recognition [19, 20, 26, 27].”
BackgroundInfluentialDevelopment of a Unique Small Molecule Modulator of CXCR4
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“speculation that small molecule antagonists can inhibit functional signal transduction without displacement of CXCL12 because CXCL12 interacts via multiple sites, one being the N-terminal segment of CXCR4 at the receptor surface [27,31].”
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“Since CXCR7 reportedly exhibits higher affinity for SDF-1 than CXCR4 (Balabanian et al., 379CXCR7 SIGNALING IN ASTROCYTES GLIA 2005; Crump et al., 1997), it is noteworthy that changes in [Ca21]i were also undetectable in CXCR7-depleted astrocytes following treatment with higher concentration of the…”
BackgroundInfluentialStructural Analysis of Chemokine Receptor–Ligand Interactions
Arimont, M., Sun, S., Leurs, R., Smit, M. J., de Esch, I. J. P., & de Graaf, C. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01309 · Cited by 126
Regulation of the Immune Response by the Interaction of Chemokines and Proteases
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The structural role of receptor tyrosine sulfation in chemokine recognition
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“The proposed two-step model for chemokine binding and activation of chemokine receptors (Crump et al., 1997).”
BackgroundResultRecognition of a CXCR4 Sulfotyrosine by the Chemokine Stromal Cell-derived Factor-1α (SDF-1α/CXCL12)
Veldkamp, C. T., Seibert, C., Peterson, F. C., Sakmar, T. P., & Volkman, B. F. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.04.052 · Cited by 123
“Proteolytic removal of the N-terminal fusion protein yields a CXCR4 (1-38) C28A peptide (P38) that retains an N-terminal Gly-Ser dipeptide.”
BackgroundMethod
Metadata
- 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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