Structural basis of receptor sulfotyrosine recognition by a CC chemokine: the N-terminal region of CCR3 bound to CCL11/eotaxin-1

Christopher J Millard, Justin P Ludeman, Meritxell Canals, Jessica L Bridgford, Mark G Hinds, Daniel J Clayton, Arthur Christopoulos, Richard J Payne, Martin J Stone

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Trafficking of leukocytes in immune surveillance and inflammatory responses is activated by chemokines engaging their receptors. Sulfation of tyrosine residues in peptides derived from the eosinophil chemokine receptor CCR3 dramatically enhances binding to cognate chemokines. We report the structural basis of this recognition and affinity enhancement. We describe the structure of a CC chemokine (CCL11/eotaxin-1) bound to a fragment of a chemokine receptor: residues 8-23 of CCR3, including two sulfotyrosine residues. We also show that intact CCR3 is sulfated and sulfation enhances receptor activity. The CCR3 sulfotyrosine residues form hydrophobic, salt bridge and cation-pi interactions with residues that are highly conserved in CC chemokines. However, the orientation of the chemokine relative to the receptor N terminus differs substantially from those observed for two CXC chemokines, suggesting that initial binding of the receptor sulfotyrosine residues guides subsequent steps in receptor activation, thereby influencing the receptor conformational changes and signaling.
Original languageEnglish
Pages (from-to)1571 - 1581
Number of pages11
JournalStructure
Volume22
Issue number11
DOIs
Publication statusPublished - 2014

Cite this

Millard, Christopher J ; Ludeman, Justin P ; Canals, Meritxell ; Bridgford, Jessica L ; Hinds, Mark G ; Clayton, Daniel J ; Christopoulos, Arthur ; Payne, Richard J ; Stone, Martin J. / Structural basis of receptor sulfotyrosine recognition by a CC chemokine: the N-terminal region of CCR3 bound to CCL11/eotaxin-1. In: Structure. 2014 ; Vol. 22, No. 11. pp. 1571 - 1581.
@article{255e386573b44674ad06b65e0223b6e8,
title = "Structural basis of receptor sulfotyrosine recognition by a CC chemokine: the N-terminal region of CCR3 bound to CCL11/eotaxin-1",
abstract = "Trafficking of leukocytes in immune surveillance and inflammatory responses is activated by chemokines engaging their receptors. Sulfation of tyrosine residues in peptides derived from the eosinophil chemokine receptor CCR3 dramatically enhances binding to cognate chemokines. We report the structural basis of this recognition and affinity enhancement. We describe the structure of a CC chemokine (CCL11/eotaxin-1) bound to a fragment of a chemokine receptor: residues 8-23 of CCR3, including two sulfotyrosine residues. We also show that intact CCR3 is sulfated and sulfation enhances receptor activity. The CCR3 sulfotyrosine residues form hydrophobic, salt bridge and cation-pi interactions with residues that are highly conserved in CC chemokines. However, the orientation of the chemokine relative to the receptor N terminus differs substantially from those observed for two CXC chemokines, suggesting that initial binding of the receptor sulfotyrosine residues guides subsequent steps in receptor activation, thereby influencing the receptor conformational changes and signaling.",
author = "Millard, {Christopher J} and Ludeman, {Justin P} and Meritxell Canals and Bridgford, {Jessica L} and Hinds, {Mark G} and Clayton, {Daniel J} and Arthur Christopoulos and Payne, {Richard J} and Stone, {Martin J}",
year = "2014",
doi = "10.1016/j.str.2014.08.023",
language = "English",
volume = "22",
pages = "1571 -- 1581",
journal = "Structure",
issn = "0969-2126",
publisher = "Elsevier",
number = "11",

}

Structural basis of receptor sulfotyrosine recognition by a CC chemokine: the N-terminal region of CCR3 bound to CCL11/eotaxin-1. / Millard, Christopher J; Ludeman, Justin P; Canals, Meritxell; Bridgford, Jessica L; Hinds, Mark G; Clayton, Daniel J; Christopoulos, Arthur; Payne, Richard J; Stone, Martin J.

In: Structure, Vol. 22, No. 11, 2014, p. 1571 - 1581.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structural basis of receptor sulfotyrosine recognition by a CC chemokine: the N-terminal region of CCR3 bound to CCL11/eotaxin-1

AU - Millard, Christopher J

AU - Ludeman, Justin P

AU - Canals, Meritxell

AU - Bridgford, Jessica L

AU - Hinds, Mark G

AU - Clayton, Daniel J

AU - Christopoulos, Arthur

AU - Payne, Richard J

AU - Stone, Martin J

PY - 2014

Y1 - 2014

N2 - Trafficking of leukocytes in immune surveillance and inflammatory responses is activated by chemokines engaging their receptors. Sulfation of tyrosine residues in peptides derived from the eosinophil chemokine receptor CCR3 dramatically enhances binding to cognate chemokines. We report the structural basis of this recognition and affinity enhancement. We describe the structure of a CC chemokine (CCL11/eotaxin-1) bound to a fragment of a chemokine receptor: residues 8-23 of CCR3, including two sulfotyrosine residues. We also show that intact CCR3 is sulfated and sulfation enhances receptor activity. The CCR3 sulfotyrosine residues form hydrophobic, salt bridge and cation-pi interactions with residues that are highly conserved in CC chemokines. However, the orientation of the chemokine relative to the receptor N terminus differs substantially from those observed for two CXC chemokines, suggesting that initial binding of the receptor sulfotyrosine residues guides subsequent steps in receptor activation, thereby influencing the receptor conformational changes and signaling.

AB - Trafficking of leukocytes in immune surveillance and inflammatory responses is activated by chemokines engaging their receptors. Sulfation of tyrosine residues in peptides derived from the eosinophil chemokine receptor CCR3 dramatically enhances binding to cognate chemokines. We report the structural basis of this recognition and affinity enhancement. We describe the structure of a CC chemokine (CCL11/eotaxin-1) bound to a fragment of a chemokine receptor: residues 8-23 of CCR3, including two sulfotyrosine residues. We also show that intact CCR3 is sulfated and sulfation enhances receptor activity. The CCR3 sulfotyrosine residues form hydrophobic, salt bridge and cation-pi interactions with residues that are highly conserved in CC chemokines. However, the orientation of the chemokine relative to the receptor N terminus differs substantially from those observed for two CXC chemokines, suggesting that initial binding of the receptor sulfotyrosine residues guides subsequent steps in receptor activation, thereby influencing the receptor conformational changes and signaling.

UR - http://www.sciencedirect.com/science/article/pii/S0969212614002901

U2 - 10.1016/j.str.2014.08.023

DO - 10.1016/j.str.2014.08.023

M3 - Article

VL - 22

SP - 1571

EP - 1581

JO - Structure

JF - Structure

SN - 0969-2126

IS - 11

ER -