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Review
. 2015 Apr;93(4):372-83.
doi: 10.1038/icb.2015.15. Epub 2015 Feb 24.

Chemokine and chemokine receptor structure and interactions: implications for therapeutic strategies

Irina Kufareva  1 , Catherina L Salanga  1 , Tracy M Handel  1
Affiliations
Review

Chemokine and chemokine receptor structure and interactions: implications for therapeutic strategies

Irina Kufareva et al. Immunol Cell Biol. 2015 Apr.

Abstract

The control of cell migration by chemokines involves interactions with two types of receptors: seven transmembrane chemokine-type G protein-coupled receptors and cell surface or extracellular matrix-associated glycosaminoglycans. Coordinated interaction of chemokines with both types of receptors is required for directional migration of cells in numerous physiological and pathological processes. Accumulated structural information, culminating most recently in the structure of a chemokine receptor in complex with a chemokine, has led to a view where chemokine oligomers bind to glycosaminoglycans through epitopes formed when chemokine subunits come together, while chemokine monomers bind to receptors in a pseudo two-step mechanism of receptor activation. Exploitation of this structural knowledge has and will continue to provide important information for therapeutic strategies, as described in this review.

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Figures

Figure 1
Figure 1. Chemokine interactions with receptors and GAGs
(A) Central to the role of chemokines is their ability to form immobilized gradients to guide the migration of receptor bearing cells. The cartoon illustrates chemokines (yellow circles) immobilized on the luminal and basolateral endothelium. Interactions with chemokines, predominantly as oligomers, and GAGs (brown branched figures) contribute to the formation of the gradient. However, only chemokine monomers are required for activation of receptors; thus chemokine oligomers must dissociate in order to bind CKRs. (B) The general two-site model of CKR:chemokine binding involves the interaction of the receptor N-terminal domain with the core domain of the chemokine, chemokine recognition site 1 (CRS1), and the N-terminal signaling domain of the chemokine with the TM binding pocket of the receptor (CRS2). (C) CRS1 interactions in CXCR1*:CXCL8 (PDB ID 1ILP), CXCR4:CXCL12 (PDB ID 2K05), CCR3:CCL11 (PDB ID 2MPM) and CXCR4:vMIP-II (PDB ID 4RWS). The chemokines are shown as surface representations with basic residues highlighted in blue. The receptor N-termini are depicted as purple ribbons with sulfated tyrosine sidechains shown as sticks and spheres. The large purple spheres labeled “C-1” indicate the residue immediately N-terminal to the conserved Cys in the CKR N-terminus; this Cys is structurally constrained in the receptor at the mouth of the TM binding pocket and allows orientation of the “CRS1 structures” relative to the receptor TM domain. Thus the orientation of the CKR peptide in the CXCR1*:CXCL8 and CXCR4:vMIP-II structures allows the chemokine N-terminal signaling domain to be oriented in a manner compatible with the CRS2 interaction. The designation CXCR1* indicates that the CXCR1 peptoid is modified with a hexanoic acid moiety, shown as small purple sticks. (D) Structure of CXCL12 with a small molecule selected from a screen to block the CRS1 interaction by targeting the sTyr21 binding site on the chemokine.
Figure 2
Figure 2. Chemokines form diverse oligomeric structures
(A) The highly conserved tertiary structure typical of all chemokines is illustrated with a monomer subunit of CXCL8 (PDB ID 1IL8). (B) A CXC-type dimer, illustrated with CXCL8 (PDB ID 1IL8). (C) A CC-type dimer illustrated by CCL2 (PDB ID 1DOM). (D) The non-canonical XCL1 dimer (PDB ID 1J90). (E-G) GAG-binding epitopes (highlighted in blue) in the context of the CXCL12 dimer (E; PDB ID 2J7Z), the CCL2 dimer (F; PDB ID 1DOM) and the CCL2 tetramer (G; PDB ID 1DOL). In the case of CCL2, the oligomeric form favored appears to be dependent on the type of GAG present where HS stabilizes a dimer (F) and heparin stabilizes a tetramer (G). (H) Some chemokines form higher order oligomers, as illustrated by CCL4 at neutral pH. Note that CCL4 forms dimers as in (C) at low pH; thus the polymer is an assembly based on the dimer as a fundamental substructure (I) GAG-binding epitopes highlighted in the context of the CCL5 octamer.
Figure 3
Figure 3. Implications of structural information for HIV interactions and inhibition
(A) A fusion of 5P12-RANTES with a C37 peptide inhibits HIV at the prefusion stage. Top: inhibition of R5 tropic viruses by binding of 5P12-RANTES to CCR5 and the C37 peptide to gp41. Bottom: inhibition of X4 tropic viruses requires the presence of CCR5 to increase the local concentration of C37. (B) Model of a gp120:CCR5 complex. Monomeric gp120 is shown in magenta (PDB 1D 2QAD) with the C4 “bridging sheet” highlighted in orange, the V3 stem highlighted in green and the V3 crown in cyan. CCR5 (PDB ID 4MBS) is shown with a blue transparent ribbon interacting with the V3 crown; sulfated N-terminal tyrosine residues (sTyr14 and sTyr15) are shown as sticks with sulfates shown as spheres.
Figure 4
Figure 4. Chemokine receptor structures and models
Surface representations of (A) CXCR4:IT1t (PDB ID 3ODU) (B) CXCR4:CVX15 (PDB ID 3OE0) (C) CCR5:Maraviroc (PDB ID 4MBS) and (D) CXCR4:vMIP-II (PDB ID 4RWS). Receptors are shown as cut-open surfaces, colored by electrostatic potential; the bound ligands are shown as spheres. (E) Structure of CXCR4:vMIP-II. vMIP-II is shown as a surface representation with regions corresponding to CRS1, CRS1.5 and CRS2 colored green, yellow and salmon, respectively. The receptor is shown as a ribbon, with residues making substantial contacts with chemokine shown as sticks. The purple region of the receptor (CRS1) N-terminus corresponds to the same region as shown in F-H. (F) Structure of the CRS1 interaction of CXCR4:vMIP-II. The chemokine is shown as a surface representation with basic residues highlighted in blue. The receptor N-terminus visible in the electron density is shown in purple. The yellow patch indicates the conserved Cys residues. The large purple spheres labeled “C-1” indicate the residue immediately N-terminal to the conserved Cys in the CKR N-terminus; this Cys is structurally constrained in the receptor at the mouth of the TM binding pocket and allows orientation of the “CRS1 structures” relative to the receptor TM domain. (G) Model of the CRS1 interaction of CXCR4:vMIP-II in which the CXCR4 N-terminus is extended by two residues to include sTyr21, shown as red spheres. (H) Model of the CRS1 interaction of CCR5:vMIP-II, represented as in G with sTyr14 and sTyr15. (I) Model of the CRS1 interaction of CXCR4:CXCL12, represented as in G with sTyr21.
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