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X-ray Crystal Structure of Truncated Human Chemokine CCL19 (7-70)
Structural highlights
FunctionCCL19_HUMAN May play a role not only in inflammatory and immunological responses but also in normal lymphocyte recirculation and homing. May play an important role in trafficking of T-cells in thymus, and T-cell and B-cell migration to secondary lymphoid organs. Binds to chemokine receptor CCR7. Recombinant CCL19 shows potent chemotactic activity for T-cells and B-cells but not for granulocytes and monocytes. Binds to atypical chemokine receptor ACKR4 and mediates the recruitment of beta-arrestin (ARRB1/2) to ACKR4.[1] Publication Abstract from PubMedThe human chemokines CCL19 and CCL21 bind to the G protein-coupled receptor (GPCR) CCR7 and play an important role in the trafficking of immune cells as well as cancer metastasis. Conserved binding sites for sulfotyrosine residues on the receptor contribute significantly to the chemokine/GPCR interaction and have been shown to provide promising targets for new drug-discovery efforts to disrupt the chemokine/GPCR interaction and, consequently, tumor metastasis. Here, we report the first X-ray crystal structure of a truncated CCL19 (residues 7-70) at 2.50 A resolution, revealing molecular details crucial for protein-protein interactions. Although the overall structure is similar to the previously determined NMR model, there are important variations, particularly near the N terminus and the so-called 30's and 40's loops. Computational analysis using the FTMap server indicates the potential importance of these areas in ligand binding and the differences in binding hotspots compared to CCL21. NMR titration experiments using a CCR7-derived peptide (residues 5-11, TDDYIGD) further demonstrate potential receptor recognition sites, such as those near the C terminus and 40's loop, which consist of both positively charged and hydrophobic residues that may be important for receptor binding. Taken together, the X-ray, NMR, and computational analysis herein provide insights into the overall structure and molecular features of CCL19 and enables investigation into this chemokine's function and inhibitor development. Structural Insights into Molecular Recognition by Human Chemokine CCL19.,Lewandowski EM, Kroeck KG, Jacobs LMC, Fenske TG, Witt RN, Hintz AM, Ramsden ER, Zhang X, Peterson F, Volkman BF, Veldkamp CT, Chen Y Biochemistry. 2022 Mar 1;61(5):311-318. doi: 10.1021/acs.biochem.1c00759. Epub, 2022 Feb 14. PMID:35156805[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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