Chemokines structures

Swaminathan GJ, Holloway DE, Colvin RA, et al. Crystal structures of oligomeric forms of the IP-10/CXCL10 chemokine. Structure 2003 11 521-32. 

Fig. 9. Ribbon structures of the three IP-IO/CXCLIO tetramers. Two orthogonal views are shovm for each. The M-form is similar to the PF4/CXCL8 and MCP-1/CCL2 structures that contain elements of CXC and CC dimers. The T and H forms contain a novel 12-stranded / -sheet. Reprinted from Structure with copyright permission from Elsevier. Swaminathan, G. et al. (2003). Crystal structures of oligomeric forms of the IP-lO/CXCLlO chemokine. Structure 11, 521-532. (See Color Insert.)...

From what is currently known about various aspects of chemokine structural biology, several types of strategies can be envisioned for interfering with chemokine function. The most widespread approach involves... 

Horuk R, Martin A, Hesselgesser J, et al. The Duffy antigen receptor for chemokines structural analysis and expression in the bram. J Leukoc Biol 1996 59 29-38. 

Several lines of evidence favor the monomer as the functional form of the chemokine. Structural analysis conditions require very high concentrations of protein - levels 10- to 1000-fold greater than the protein concentrations needed for biological function, which may not occur in vivo. Also, mutational changes can be made in the primary structure that prevent multimerization and do not significantly affect function (Rajarathnam et al., 1994). Finally, the primary structure of vMIP-II, a virally encoded (human herpesvirus 8 or HHV8) chemokine, resembles that of MIP-la however, vMIP-II fails to dimerize regardless of the pH or protein concentration (personal communication from Barry L. Schweitzer). 

Figure 1 Chemokine structure and function. Chemokines share a common tertiary structure (here MCP-1/CCL2 is shown as an example—ribbon structure produced using jmol from PDB structure 1 DOM). The rigid, folded core of the protein carries "address" structures (CRSl) that provide high-affinity and high-specificity interactions with chemokine receptors, and the flexible N-terminal region carries "message" structures (CRS2) that affect receptor function. The C-terminus does not participate in receptor interaction and can be modified without affecting pharmacology.

Hence aside from their potential for development as anti-HIV medicines, this set of analogs represents a valuable toolbox that can be used to better understand chemokine structure—activity relationships, particularly now that crystal structures of chemokine—chemokine receptor complexes are becoming available (Qin et al., 2015 Burg et al., 2015). 

All of the CXC ligand proteins are active as chemoattractant factors. As mentioned earlier, the first chemokine identified was CXCLS, which has now been extensively characterized and will thus be used as a representative for this discussion on chemokine structures and functions. The amino-acid alignment of all the human CXC chemokines shown in Fig. 2 is therefore arranged with respect to CXCLS, and references to specific sections of CXCLs will be numbered according to the CXCLS primary sequence. 

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