Structure, Function, and Inhibition of Chemokines

Abstract

Chemokines are the largest family of cytokines in human immunophysiology. These proteins are defined by four invariant cysteines and are categorized based on the sequence around the first two cysteines, which leads to two major and two minor subfamilies. Chemokines function by activating specific G protein-coupled receptors, which results in, among other functions, the migration of inflammatory and noninflammatory cells to the appropriate tissues or compartments within tissues. Some of these proteins and receptors have been implicated or shown to be involved in inflammation, autoimmune diseases, and infection by HIV-1. The three-dimensional structure of each monomer is virtually identical, but the quaternary structure of chemokines is different for each subfamily. Structure-function studies reveal several regions of chemokines to be involved in function, with the N-terminal region playing a dominant role. A number of proteins and small-molecule antagonists have been identified that inhibit chemokine activities. In this review, we discuss aspects of the structure, function, and inhibition of chemokines.

Antagonist of interferon‐inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice

“…N-terminal-truncated or modified chemokine analogs have been reported to act as receptor antagonists (for review, see ref. 25). To examine the role of the N-terminal region of murine IP-10 in determining func- tionality, we designed a series of analogs that were shortened at the N-terminal.…”

“…In chemokines it has been observed that the N-terminal region is essential for functional activity and that the loop immediately following the first 2 cysteines in the sequence, as well as the N-terminal region, has an important role in receptor binding (25). Truncation or modification of a few N-terminal amino acids in several chemokines, such as MCP-1, MCP-2, RANTES, IL-8, Fkn, and secondary lymphoid-tissue chemokine/CCL21, has been reported to lead to significant changes in functional activity and receptor binding (11,24,25).…”

“…Truncation or modification of a few N-terminal amino acids in several chemokines, such as MCP-1, MCP-2, RANTES, IL-8, Fkn, and secondary lymphoid-tissue chemokine/CCL21, has been reported to lead to significant changes in functional activity and receptor binding (11,24,25). Analogs of IP-10 that were truncated by 5 or more amino acid residues from the N-terminal showed loss of biologic activity but retained their receptor-binding capability.…”

Molecular characterization and expression profiles in response to bacterial infection of Chinese soft-shelled turtle interleukin-8 (IL-8), the first reptilian chemokine gene

“…CXC chemokines can be subdivided into two groups based on the presence of the Glu-Leu-Arg (ELR) motif which is critical for receptor binding and signaling [3,4]. The chemokines containing the ELR motif (ELR + ) like IL-8 preferentially attract neutrophils, while the CXC chemokines without an ELR motif (ELR À ) mainly attract lymphocytes and monocytes [5,6].…”

Prodrugs of a CXC Chemokine-12 (CXCL12) Neutraligand Prevent Inflammatory Reactions in an Asthma Model in Vivo

“…1 In screening a proprietary chemical library, 2 we recently identified compounds belonging to the chalcone family and preventing CXCL12 from binding to its CXCR4 or CXCR7 receptors. 3 These compounds have an original mechanism of action: they bind to the chemokine rather than to the receptors.…”