Selective Allosteric Modulation of N-Terminally Cleaved, but Not Full Length CCL3 in CCR1
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Selective Allosteric Modulation of N-Terminally Cleaved, but Not Full Length CCL3 in CCR1. / Larsen, Olav; Lückmann, Michael; van der Velden, Wijnand J.C.; Oliva-Santiago, Marta; Brvar, Matjaz; Ulven, Trond; Frimurer, Thomas M; Karlshøj, Stefanie; Rosenkilde, Mette M.
In: ACS Pharmacology & Translational Science, Vol. 2, No. 6, 2019, p. 429-441.Research output: Contribution to journal › Letter › Research › peer-review
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TY - JOUR
T1 - Selective Allosteric Modulation of N-Terminally Cleaved, but Not Full Length CCL3 in CCR1
AU - Larsen, Olav
AU - Lückmann, Michael
AU - van der Velden, Wijnand J.C.
AU - Oliva-Santiago, Marta
AU - Brvar, Matjaz
AU - Ulven, Trond
AU - Frimurer, Thomas M
AU - Karlshøj, Stefanie
AU - Rosenkilde, Mette M
N1 - Copyright © 2019 American Chemical Society.
PY - 2019
Y1 - 2019
N2 - Chemokines undergo post-translational modification such as N-terminal truncations. Here, we describe how N-terminal truncation of full length CCL3(1-70) affects its activity at CCR1. Truncated CCL3(5-70) has 10-fold higher potency and enhanced efficacy in β-arrestin recruitment, but less than 2-fold increased potencies in G protein signaling determined by calcium release, cAMP and IP3 formation. Small positive ago-allosteric ligands modulate the two CCL3 variants differently as the metal ion chelator bipyridine in complex with zinc (ZnBip) enhances the binding of truncated, but not full length CCL3, while a size-increase of the chelator to a chloro-substituted terpyridine (ZnClTerp), eliminates its allosteric, but not agonistic action. By employing a series of receptor mutants and in silico modeling we describe residues of importance for chemokine and small molecule binding. Notably, the chemokine receptor-conserved Glu2877.39 interacts with the N-terminal amine of truncated CCL3(5-70) and with Zn2+ of ZnBip, thereby bridging their binding sites and enabling the positive allosteric effect. Our study emphasizes that small allosteric molecules may act differently toward chemokine variants and thus selectively modulate interactions of specific chemokine subsets with their cognate receptors.
AB - Chemokines undergo post-translational modification such as N-terminal truncations. Here, we describe how N-terminal truncation of full length CCL3(1-70) affects its activity at CCR1. Truncated CCL3(5-70) has 10-fold higher potency and enhanced efficacy in β-arrestin recruitment, but less than 2-fold increased potencies in G protein signaling determined by calcium release, cAMP and IP3 formation. Small positive ago-allosteric ligands modulate the two CCL3 variants differently as the metal ion chelator bipyridine in complex with zinc (ZnBip) enhances the binding of truncated, but not full length CCL3, while a size-increase of the chelator to a chloro-substituted terpyridine (ZnClTerp), eliminates its allosteric, but not agonistic action. By employing a series of receptor mutants and in silico modeling we describe residues of importance for chemokine and small molecule binding. Notably, the chemokine receptor-conserved Glu2877.39 interacts with the N-terminal amine of truncated CCL3(5-70) and with Zn2+ of ZnBip, thereby bridging their binding sites and enabling the positive allosteric effect. Our study emphasizes that small allosteric molecules may act differently toward chemokine variants and thus selectively modulate interactions of specific chemokine subsets with their cognate receptors.
U2 - 10.1021/acsptsci.9b00059
DO - 10.1021/acsptsci.9b00059
M3 - Letter
C2 - 32259075
VL - 2
SP - 429
EP - 441
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
SN - 2575-9108
IS - 6
ER -
ID: 239724026