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Review
. 2017 Oct 2;18(10):2088.
doi: 10.3390/ijms18102088.

Chemokines from a Structural Perspective

Michelle C Miller  1 , Kevin H Mayo  2
Affiliations
Review

Chemokines from a Structural Perspective

Michelle C Miller et al. Int J Mol Sci. .

Abstract

Chemokines are a family of small, highly conserved cytokines that mediate various biological processes, including chemotaxis, hematopoiesis, and angiogenesis, and that function by interacting with cell surface G-Protein Coupled Receptors (GPCRs). Because of their significant involvement in various biological functions and pathologies, chemokines and their receptors have been the focus of therapeutic discovery for clinical intervention. There are several sub-families of chemokines (e.g., CXC, CC, C, and CX3C) defined by the positions of sequentially conserved cysteine residues. Even though all chemokines also have a highly conserved, three-stranded β-sheet/α-helix tertiary structural fold, their quarternary structures vary significantly with their sub-family. Moreover, their conserved tertiary structures allow for subunit swapping within and between sub-family members, thus promoting the concept of a "chemokine interactome". This review is focused on structural aspects of CXC and CC chemokines, their functional synergy and ability to form heterodimers within the chemokine interactome, and some recent developments in structure-based chemokine-targeted drug discovery.

Keywords: NMR; chemokine; heterodimers; interactome; structure.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Superposition of seven monomer subunits from reported structures of CXC and CC chemokine homodimers is shown: CXCL4 M2 variant (Protein Data Bank, PDB: 1PFM), CXCL8 (PDB: 1IL8), CXCL12 (PDB: 3HP3), CXCL13 (PDB: 4ZAI), CCL5 (PDB: 5COY), CCL14 (PDB: 2Q8R), and CCL20 (PDB: 1HA6). (A) Only atoms within the three-stranded β-sheet are superimposed with RMSD values ranging between ~1.3 and ~1.7 Å; (B) Superimposed structures shown in panel A are rotated by about 180° to illustrate how C-terminal helices are folded onto the β-sheet at somewhat different angles.
Figure 2
Figure 2
Structures of CXC chemokine CXCL8 (Interleukin-8, PDB access code 1IL8, [10]) (panel A) and CC chemokine CCL5 (RANTES, PDB access code 5COY, [17]) (panel B) are shown. Two orientations of the CXCL4 M2 tetramer structure (platelet factor-4, PF4; PDB access code 1PFM, [18]) are shown in panels (C,D). C-terminal helices are colored red, and the remaining sequences are colored cyan.
Figure 3
Figure 3
Higher-order oligomer structures of CCL5. (A) Proposed oligomer structure of CCL5 deduced from analysis of NMR, MS, and SAXS data (PDB access code: 2L9H, [15]; (B) Modeled oligomer structure of CCL3 (PDB access code: 5L2U, [17]) is shown to illustrate how a CC-type dimer could associate in a somewhat different fashion into a higher order oligomer. C-terminal helices are colored red; β-strands are colored yellow, and aperiodic sequences/loops are colored green.
Figure 4
Figure 4
Modeled structures of CXCL4/CCL5 heterodimers. These structures are based on NMR chemical shift and intensity changes from HSQC experiments on CXCL4 and CCL5. NMR data were used to direct manual docking and energy minimization using Molecular Dynamics (MD) simulations, as discussed in von Hundelshausen et al. [42]. MD simulations and energy minimization were done with CCL5 and CXCL4 monomer subunits initially docked as a CXC-type dimer (A) or a CC-type dimer (B), with the CC-type heterodimer being energetically favored. CXCL4 monomer subunits are shown in red, and CCL5 monomer subunits are shown in blue. These structures were produced by Dr. Kanin Wichapong, Maastricht University, The Netherlands.
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