Crystallographic Structure of Truncated CCL21 and the Putative Sulfotyrosine-Binding Site. Biochemistry 2016 Oct 11;55(40):5746-5753
Date
09/13/2016Pubmed ID
27617343Pubmed Central ID
PMC5498006DOI
10.1021/acs.biochem.6b00304Scopus ID
2-s2.0-84991072808 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
CCL21 chemokine binds the G protein-coupled receptor CCR7, aiding not only in immune response but also in cancer metastasis. Compared with other chemokines, CCL21 has a unique extended unstructured C-terminus that is truncated in some naturally occurring variants. We have determined the X-ray crystallographic structure of a truncated CCL21 (residues 1-79) lacking the extended C-terminus and identified, via two-dimensional nuclear magnetic resonance (NMR), a putative sulfotyrosine-binding site that may recognize such post-translationally modified tyrosine residues on the receptor. Compared to the previously determined NMR structure of full-length CCL21, the crystal structure presents new druggable binding hot spots resulting from an alternative N-loop conformation. In addition, whereas the previous NMR structure did not provide any structural information after residue 70, the C-terminus of the truncated CCL21, ordered up to Ala77 in our crystal structure, is placed near the N-loop and sulfotyrosine-binding site, indicating that the extended C-terminus of full-length CCL21 can interact with this important region for receptor binding. These observations suggest a potential origin for the autoinhibition of CCL21 activity that was recently described. The new crystal structure and binding hot spot analysis have important implications for the function of the CCL21 C-terminus and drug discovery.
Author List
Smith EW, Lewandowski EM, Moussouras NA, Kroeck KG, Volkman BF, Veldkamp CT, Chen YAuthor
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Binding SitesChemokine CCL21
Crystallography, X-Ray
Nuclear Magnetic Resonance, Biomolecular
Protein Conformation
Tyrosine
