Structural basis of chemokine and receptor interactions: Key regulators of leukocyte recruitment in inflammatory responses

Abstract

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Semisynthesis of an evasin from tick saliva reveals a critical role of tyrosine sulfation for chemokine binding and inhibition

“…However, the development of such therapeutic candidates would require overcoming the usual challenges of protein therapeutics (e.g., stability, delivery, bioavailability, and immunogenicity) as well as improving our understanding of the factors influencing the chemokine affinity and selectivity of evasin proteins. The two families of evasins have distinct structures and chemokine selectivity (39). Homologs of evasin-1 and evasin-4 (class A evasins), such as ACA-01, exclusively target CC chemokines, which are characterized by a pair of adjacent cysteine residues near the protein N terminus (20,21).…”

“…Sulfopeptides derived from the N-terminal regions of CCR3 and CCR5 interact with the same regions of their cognate chemokines ( Fig. 7 B and C) (47,48), although the orientations of the sulfopeptides in these complexes may not be truly reflective of the orientation with which the actual receptor N terminus binds to the chemokines (39). Nevertheless, based on the structure of CCR5 bound to chemokine variant 5P7-CCL5 (46), it appears likely that the orientation of the receptor N terminus is similar to that of the evasin-1 N terminus in complex with CCL3 ( Fig.…”

Long-range coupled motions underlie ligand recognition by a chemokine receptor

“…The past decade has seen an explosion of GPCR including chemokine receptor structures that can be attributed to advances in receptor expression and folding, reconstitution with detergents, and constructs that are stable and more amenable to crystallization (Kruse et al, 2013;Rosenbaum et al, 2007). The latter technology includes replacing a flexible IC loop with T4 lysozyme, using nanobodies to stabilize a specific conformer, and/or solving the structure bound to agonists, antagonists, and/or small molecule inhibitors that were critical for determining chemokine receptor structures and generating structural models (Bhusal et al, 2020;Wu et al, 2010;Zheng et al, 2016). These structures represent snapshots and are not sufficient for providing a spatiotemporal description of how the chemokine bound at Site-I searches and binds the residues at Site-II.…”

“…Chemokines, in turn, show a range of receptor specificity and activity. Diversity of interactions is further compounded by chemokines and chemokine receptors existing as monomers and dimers, biased G protein vs. barrestin signaling, interacting with glycosaminoglycans, post-translational modification, and binding to atypical chemokine receptors (Bhusal et al, 2020;Rajagopal et al, 2013;Rajarathnam and Desai, 2020).…”

Chemical synthesis of a haemathrin sulfoprotein library reveals enhanced thrombin inhibition following tyrosine sulfation

“…[5][6][7][8] While Tyr sulfation has been discovered as a crucial modification on a number of proteins, including several key players in the inflammatory and immune response, the inherent acid lability of the phenolic sulfate ester means that the modification is difficult to retain on the protein during isolation and/or detect by modern mass spectrometric methods. 4,9,10 As such, it is likely that native sulfation of many proteins has been overlooked during isolation or is yet to be identified. 10 A key example where this has been the case is the ''sialome'' of hematophagous organisms.…”