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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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Molecular characterization of sdf1 and cxcr4 in the Mozambique tilapia, Oreochromis mossambicus
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“Consistent with a constrained role in receptor binding (Crump et al., 1997), there is strong conservation of the N-terminal Lys-Pro residues and less conservation within the RFFESH human cxcr4 binding motif.”
BackgroundJanssens, R., Boff, D., Ruytinx, P., Mortier, A., Vanheule, V., Larsen, O., Daugvilaite, V., ROSENKILDE, M. M., Noppen, S., Liekens, S., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01933 · Cited by 7
Targeting CXCL12/CXCR4 Axis in Multiple Myeloma
Pandey, M. K. (2014) · Journal of Hematology & Thromboembolic Diseases · doi:10.4172/2329-8790.1000159 · Cited by 7
“In a two-step model the first step constitutes recognition and binding of chemokine to the receptor followed by conformational change in the chemokine at N terminus which then can act as a guanine nucleotide exchange factor leading to exchange of bound GDP for GTP in α subunit of the G proteins [51].”
BackgroundFunction of Chemokines and Their Receptors in Immunity
Thelen, M., & Uguccioni, M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-374279-7.10008-6 · Cited by 7
Interaction and dynamics of chemokine receptor CXCR4 binding with CXCL12 and hBD-3
Penfield, J., & Zhang, L. (2024) · Communications Chemistry · doi:10.1038/s42004-024-01280-6 · Cited by 6
“This is consistent with fi ndings from Crump et al. 27 who found that CXCL12 should have the N-terminus reaching the orthosteric pocket of CXCR4.”
BackgroundMethodResultInfluentialYang, Q., Chen, C., Yang, Z., Gao, Y., & Tang, J. (2011) · Journal of Huazhong University of Science and Technology [Medical Sciences] · doi:10.1007/s11596-011-0479-z · Cited by 6
“The interaction between SDF-1α and CXCR4 has been proposed to occur through a two-step process [ 20 ] . The initial interaction between residues 12–17 of SDF-1α and 2–36 of CXCR4 are believed to result in a conformational change in the receptor”
BackgroundBromage, D. I., Taferner, S., Pillai, M. G.-K., Yellon, D. M., & Davidson, S. M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0174447 · Cited by 6
“As loss of the N-terminal Lys(1) is known to confer a complete loss of bioreactivity,[23] the incomplete detection of SDF-1α by Fig 8.”
BackgroundAllosteric modulation of the chemokine receptor-chemokine CXCR4-CXCL12 complex by tyrosine sulfation
Sonawani, A., Kharche, S., Dasgupta, D., & Sengupta, D. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.03.078 · Cited by 6
Discovery of Bis-Imidazoline Derivatives as New CXCR4 Ligands
Zhou, Z., Staropoli, I., Brelot, A., Suzanne, P., Lesnard, A., Fontaine, F., Perato, S., Rault, S., Helynck, O., Arenzana‐Seisdedos, F., et al. (2023) · Molecules · doi:10.3390/molecules28031156 · Cited by 6
“As previously observed, P2G showed weaker anti-HIV-1 potency than CXCL12 due to its inability to internalize CXCR4 [51,56].”
BackgroundMethodSelf-citationSpecificity determinants for chemokine recognition identified using eotaxin‐MCP‐1 chimeras
Mayer, M. R., Parody, T. R., Datta‐Mannan, A., & Stone, M. J. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.06.079 · Cited by 6
Structural insight into the evolution of a new chemokine family from zebrafish
Rajasekaran, D., Fan, C., Meng, W., Pflugrath, J. W., & Lolis, E. (2013) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.24380 · Cited by 6
Generation and characterization of mice harboring a conditional CXCL12 allele
Hillmer, R. E., Boisvert, J. P., Cucciare, M. J., Dwinell, M. B., & Joksimovic, M. (2015) · The International Journal of Developmental Biology · doi:10.1387/ijdb.140348mj · Cited by 6
Hattori, H., Amano, Y., Habu-Ogawa, Y., Ando, T., Takase, B., & Ishihara, M. (2013) · Cell Transplantation · doi:10.3727/096368912x658863 · Cited by 6
“Wound healing is inhibited if SDF-1 or CXCR4+ cells are blocked in ischemic tissues (8).”
BackgroundInfluentialMultiple binding modes of an N‐terminal CCR5‐peptide in complex with HIV‐1 gp120
Moseri, A., Akabayov, S. R., Cohen, L. S., Naider, F. R., & Anglister, J. (2021) · FEBS Journal · doi:10.1111/febs.16328 · Cited by 6
Crystal structure of chemically synthesized vMIP‐II
Li, Y., Liu, D., Cao, R., Kumar, S., Dong, C., An, J., Wilson, S. R., Gao, Y., & Huang, Z. (2007) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.21172 · Cited by 6
Palladino, P., Tizzano, B., Pedone, C., Ragone, R., Rossi, F., Saviano, G., Tancredi, T., & Benedetti, E. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.07.100 · Cited by 6
“The RFFESH sequence, located in the loop region of SDF-1a at positions 12–17, is necessary for optimal binding, but not sufficient for receptor activation [3].”
BackgroundResultInfluentialSandoval, C., Stojanova, A., DiFalco, M. R., & Congote, L. F. (2003) · Biochemical Pharmacology · doi:10.1016/s0006-2952(03)00207-7 · Cited by 6
Anti-chemokine antibodies after SARS-CoV-2 infection correlate with favorable disease coursePreprint
Muri, J., Cecchinato, V., Cavalli, A., Shanbhag, A. A., Matkovic, M., Biggiogero, M., Maida, P. A., Moritz, J., Toscano, C., Ghovehoud, E., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.23.493121 · Cited by 6
Ludwig‐Husemann, A., Schertl, P., Shrivastava, A., Geckle, U., Hafner, J., Schaarschmidt, F., Willenbacher, N., Freudenberg, U., Werner, C., & Lee‐Thedieck, C. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202304157 · Cited by 5
Chertov, O., Zhang, N., Chen, X., Oppenheim, J. J., Lubkowski, J. T., McGrath, C. F., Sowder, R. C., Crise, B. J., Malyguine, A. M., Kutzler, M. A., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0014474 · Cited by 5
CXCR4-targeted metal complexes for molecular imaging
Renard, I., & Archibald, S. J. (2020) · Advances in inorganic chemistry · doi:10.1016/bs.adioch.2019.11.002 · Cited by 5
Structural Insights into Molecular Recognition by Human Chemokine CCL19
Lewandowski, E. M., Kroeck, K. G., Jacobs, L. M. C., Fenske, T. G., Witt, R. N., Hintz, A. M., Ramsden, E. R., Zhang, X., Peterson, F. C., Volkman, B. F., et al. (2022) · Biochemistry · doi:10.1021/acs.biochem.1c00759 · Cited by 7
Chemokines and nanomaterials: interaction for useful immune-applications
Bardi, G. (2022) · Exploration of Immunology · doi:10.37349/ei.2022.00073 · Cited by 5
“00073 Page 638 the downstream signal transduction, as firstly demonstrated for CXCL12/Cys-aminoacid X-Cys chemokine receptor 4 (CXCR4) binding [6].”
BackgroundOkamoto, R., Mandal, K., Ling, M. F., Luster, A. D., Kajihara, Y., & Kent, S. B. H. (2014) · Angewandte Chemie · doi:10.1002/ange.201310574 · Cited by 5
Chemokines: A New Peptide Family of Neuromodulators
Kitabgi, P., Parsadaniantz, S. M., & Rostène, W. H. (2006) · Elsevier eBooks · doi:10.1016/b978-012369442-3/50083-0 · Cited by 5
Zhang, W., Wang, X., Yue, K., Liu, S., & Liu, X. (2015) · BioMed Research International · doi:10.1155/2015/195828 · Cited by 5
“Research Article Construction of a CXCL12-KDEL Fusion Gene to Inhibit Head and Neck Squamous Cell Carcinoma Metastasis by Intracellular Sequestration of CXCR4 Wenchao Zhang, Xudong Wang, Kai Yue, Su Liu, and Xiaonan Liu Department of Maxillofacial and ENT, National Cancer Clinical Research Center, Tianjin Medical Univ…”
BackgroundN-terminal domain of eotaxin-3 is important for activation of CC chemokine receptor 3
Shinkai, A., Komuta-Kunitomo, M., Sato-Nakamura, N., & Anazawa, H. (2002) · Protein Engineering Design and Selection · doi:10.1093/protein/15.11.923 · Cited by 5
“These structural features are conserved among the chemokine molecules of which the structures have been determined so far (Baldwin et al., 1991; Lodi et al., 1994; Skelton et al., 1995; Handel and Domaille, 1996; Crump et al., 1997, 1998; Mayer and Stone, 2000).”
BackgroundMethodResultInfluentialIntroduction to Chemokines and Chemokine Antagonists
Baggiolini, M. (2004) · Springer eBooks · doi:10.1007/978-3-662-05403-1_1 · Cited by 5
Self-citationEgorova, A., Freund, S., Krylova, Y. S., Kislova, A. V., & Kiselev, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262110582 · Cited by 6
“It should be noted that the process of the receptor-ligand binding is well understood, and specific peptide sequences have been developed for targeting CXCR4 [25–27].”
Michalska, Z., Ostaszewska, A., Fularczyk, M., Dzierżyńska, M., Bielak, K., Morytz, J., Sieradzan, A. K., Archacka, K., Brzóska, E., Rodziewicz‐Motowidło, S., et al. (2025) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.37898 · Cited by 4
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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