5DNF

Crystal structure of CC chemokine 5 (CCL5) oligomer in complex with heparin

Summary for 5DNF

• Entry DOI: 10.2210/pdb5dnf/pdb
• Related: 5CMD 5COY
• Descriptor: C-C motif chemokine 5, 2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose, alpha-D-galactopyranose, ... (8 entities in total)
• Functional Keywords: cc chemokine, high oligomer, cytokine
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 9
• Total formula weight: 73675.35

Authors

Liang, W.G.,Tang, W. (deposition date: 2015-09-10, release date: 2016-04-13, Last modification date: 2024-10-09)

Primary citation

Liang, W.G.,Triandafillou, C.G.,Huang, T.Y.,Zulueta, M.M.,Banerjee, S.,Dinner, A.R.,Hung, S.C.,Tang, W.J.
Structural basis for oligomerization and glycosaminoglycan binding of CCL5 and CCL3.
Proc.Natl.Acad.Sci.USA, 113:5000-5005, 2016

PubMed Abstract: CC chemokine ligand 5 (CCL5) and CCL3 are critical for immune surveillance and inflammation. Consequently, they are linked to the pathogenesis of many inflammatory conditions and are therapeutic targets. Oligomerization and glycosaminoglycan (GAG) binding of CCL5 and CCL3 are vital for the functions of these chemokines. Our structural and biophysical analyses of human CCL5 reveal that CCL5 oligomerization is a polymerization process in which CCL5 forms rod-shaped, double-helical oligomers. This CCL5 structure explains mutational data and offers a unified mechanism for CCL3, CCL4, and CCL5 assembly into high-molecular-weight, polydisperse oligomers. A conserved, positively charged BBXB motif is key for the binding of CC chemokines to GAG. However, this motif is partially buried when CCL3, CCL4, and CCL5 are oligomerized; thus, the mechanism by which GAG binds these chemokine oligomers has been elusive. Our structures of GAG-bound CCL5 and CCL3 oligomers reveal that these chemokine oligomers have distinct GAG-binding mechanisms. The CCL5 oligomer uses another positively charged and fully exposed motif, KKWVR, in GAG binding. However, residues from two partially buried BBXB motifs along with other residues combine to form a GAG-binding groove in the CCL3 oligomer. The N termini of CC chemokines are shown to be involved in receptor binding and oligomerization. We also report an alternative CCL3 oligomer structure that reveals how conformational changes in CCL3 N termini profoundly alter its surface properties and dimer-dimer interactions to affect GAG binding and oligomerization. Such complexity in oligomerization and GAG binding enables intricate, physiologically relevant regulation of CC chemokine functions.

PubMed: 27091995
DOI: 10.1073/pnas.1523981113

Experimental method

X-RAY DIFFRACTION (2.549 Å)