scholarly journals Small Molecule Receptor Agonists and Antagonists of CCR3 Provide Insight into Mechanisms of Chemokine Receptor Activation

2007 ◽  
Vol 282 (38) ◽  
pp. 27935-27943 ◽  
Author(s):  
Emma L. Wise ◽  
Cécile Duchesnes ◽  
Paula C. A. da Fonseca ◽  
Rodger A. Allen ◽  
Timothy J. Williams ◽  
...  
Keyword(s):  
Small Molecule ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Direct Interaction ◽  
Receptor Activation ◽  
Transmembrane Helices ◽  
Small Molecule Libraries ◽  
Chemokine Receptor Ccr3 ◽  
Allergic Disorders ◽  
Receptor Agonists And Antagonists

Chemokine receptor CCR3 is highly expressed by eosinophils and signals in response to binding of the eotaxin family of chemokines, which are up-regulated in allergic disorders. Consequently, CCR3 blockade is of interest as a possible therapeutic approach for the treatment of allergic disease. We have described previously a bispecific antagonist of CCR1 and CCR3 named UCB35625 that was proposed to interact with the transmembrane residues Tyr-41, Tyr-113, and Glu-287 of CCR1, all of which are conserved in CCR3. Here, we show that cells expressing the CCR3 constructs Y113A and E287Q are insensitive to antagonism by UCB35625 and also exhibit impaired chemotaxis in response to CCL11/eotaxin, suggesting that these residues are important for antagonist binding and also receptor activation. Furthermore, mutation of the residue Tyr-113 to alanine was found to turn the antagonist UCB35625 into a CCR3 agonist. Screens of small molecule libraries identified a novel specific agonist of CCR3 named CH0076989. This was able to activate eosinophils and transfectants expressing both wild-type CCR3 and a CCR1–CCR3 chimeric receptor lacking the CCR3 amino terminus, indicating that this region of CCR3 is not required for CH0076989 binding. A direct interaction with the transmembrane helices of CCR3 was supported by mutation of the residues Tyr-41, Tyr-113, and Glu-287 that resulted in complete loss of CH0076989 activity, suggesting that the compound mimics activation by CCL11. We conclude that both agonists and antagonists of CCR3 appear to occupy overlapping sites within the transmembrane helical bundle, suggesting a fine line between agonism and antagonism of chemokine receptors.

Unravelling the mechanisms underpinning chemokine receptor activation and blockade by small molecules: a fine line between agonism and antagonism?

2007 ◽  
Vol 35 (4) ◽  
pp. 755-759 ◽  
Author(s):  
E. Wise ◽  
J.E. Pease
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Considerable Effort ◽  
G Protein Coupled ◽  
Migration Of Cells

Chemokines are a family of small basic proteins which induce the directed migration of cells, notably leucocytes, by binding to specific GPCRs (G-protein-coupled receptors). Both chemokines and their receptors have been implicated in a host of clinically important diseases, leading to the notion that antagonism of the chemokine–chemokine receptor network may be therapeutically advantageous. Consequently, considerable effort has been put into the development of small-molecule antagonists of chemokine receptors and several such compounds have been described in the literature. One curious by-product of this activity has been the description of several small-molecule agonists of the receptors, which are typically discovered following the optimization of lead antagonists. In this review we discuss these findings and conclude that these small-molecule agonists might be exploited to further our understanding of the molecular mechanisms by which chemokine receptors are activated.

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

2020 ◽  
Author(s):  
Krishna Mohan Sepuru ◽  
Vinay Nair ◽  
Priyanka Prakash ◽  
Alemayehu A. Gorfe ◽  
Krishna Rajarathnam
Keyword(s):  
Chemokine Receptor ◽  
Md Simulations ◽  
Active Role ◽  
Receptor Activation ◽  
Ligand Recognition ◽  
Transmembrane Helices ◽  
Class A ◽  
Binding Interface ◽  
Receptor Sites

AbstractChemokines are unusual class-A GPCR agonists because of their large size (∼10 kDa) and binding at two distinct receptor sites: N-terminal domain (Site-I, unique to chemokines) and a groove defined by extracellular loop/transmembrane helices (Site-II, shared with all small molecule class-A ligands). Whereas binding at Site-II triggers receptor activation, the role of Site-I is not known. Structures and sequence analysis reveal that the receptor N-terminal domains (N-domains) are flexible and contain intrinsic disorder. Using a hybrid NMR-MD approach, we characterized the role of Site-I interactions for the CXCL8-CXCR1 pair. NMR data indicate that the CXCR1 N-domain becomes structured on binding and that the binding interface is extensive with 30% of CXCL8 residues participating in this initial interaction. MD simulations indicate that CXCL8 bound at Site-I undergoes extensive reorganization on engaging Site-II with several residues initially engaged at Site-I also engaging Site-II. We conclude that structural plasticity of Site-I interactions plays an active role in driving ligand recognition by a chemokine receptor.

scholarly journals Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 8
Author(s):  
Paulina Lewandowska ◽  
Jaroslaw Wierzbicki ◽  
Marek Zawadzki ◽  
Anil Agrawal ◽  
Małgorzata Krzystek-Korpacka
Keyword(s):  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Chemokine Receptor ◽  
Growth Pattern ◽  
Chemokine Receptors ◽  
Receptor Expression ◽  
Transcriptional Analysis ◽  
Neoplastic Tissue ◽  
Node Metastasis ◽  
Affected Tissue

Facilitating resolution of inflammation using atypical chemokine receptors (ACKR) as an anticancer strategy is considered but requires a deeper understanding of receptor role in carcinogenesis. We aimed at transcriptional analysis (RTqPCR) of ACKR2 and ACKR4 expression in colorectal adenoma-adenocarcinoma sequence in paired normal-neoplastic tissues from 96 polyps and 51 cancers. On average, ACKR2 was downregulated in neoplastic as compared to non-affected tissue in polyp (by 2.7-fold) and cancer (by 3.1-fold) patients. The maximal downregulation (by 8.2-fold) was observed in adenomas with the highest potential for malignancy and was gradually lessening through cancer stages I-IV, owing to increased receptor expression in tumors. On average, ACKR4 was significantly downregulated solely in adenocarcinomas (by 1.5-fold), less so in patients with lymph node metastasis, owing to a gradual decrease in ACKR4 expression among N0-N1-N2 cancers in non-affected tissue without changes in tumors. In adenomas, ACKR4 downregulation in neoplastic tissue increased with increasing potential for malignancy and contribution of villous growth pattern. ACKR4 expression increased in non-affected tissue with a concomitant decrease in pathological mucosa. In conclusion, the changes in ACKRs expression occur already in precancerous colorectal lesions, culminating in the adenomas with the highest potential for malignancy. Therefore, chemoprevention by manipulating ACKRs’ expression is worth exploration.

scholarly journals Antimicrobial Peptides and Physical Activity: A Great Hope against COVID 19

2021 ◽  
Vol 9 (7) ◽  
pp. 1415
Author(s):  
Sonia Laneri ◽  
Mariarita Brancaccio ◽  
Cristina Mennitti ◽  
Margherita G. De Biasi ◽  
Maria Elena Pero ◽  
...  
Keyword(s):  
Physical Activity ◽  
Antimicrobial Peptides ◽  
Intracellular Signaling ◽  
Chemokine Receptors ◽  
Healthy Lifestyle ◽  
Direct Interaction ◽  
Vaccine Adjuvants ◽  
Viral Inhibition ◽  
Immune Modulators ◽  
Surface Receptors

Antimicrobial peptides (AMPs), α- and β-defensins, possess antiviral properties. These AMPs achieve viral inhibition through different mechanisms of action. For example, they can: (i) bind directly to virions; (ii) bind to and modulate host cell-surface receptors, disrupting intracellular signaling; (iii) function as chemokines to augment and alter adaptive immune responses. Given their antiviral properties and the fact that the development of an effective coronavirus disease 2019 (COVID-19) treatment is an urgent public health priority, they and their derivatives are being explored as potential therapies against COVID-19. These explorations using various strategies, range from their direct interaction with the virus to using them as vaccine adjuvants. However, AMPs do not work in isolation, specifically in their role as potent immune modulators, where they interact with toll-like receptors (TLRs) and chemokine receptors. Both of these receptors have been shown to play roles in COVID-19 pathogenesis. In addition, it is known that a healthy lifestyle accompanied by controlled physical activity can represent a natural weapon against COVID-19. In competitive athletes, an increase in serum defensins has been shown to function as self-protection from the attack of microorganisms, consequently a controlled physical activity could act as a support to any therapies in fighting COVID-19. Therefore, including information on all these players’ interactions would produce a complete picture of AMP-based therapies’ response.

scholarly journals Screening of DNA-Encoded Small Molecule Libraries inside a Living Cell

2021 ◽  
Vol 143 (7) ◽  
pp. 2751-2756
Author(s):  
Lars K. Petersen ◽  
Allan B. Christensen ◽  
Jacob Andersen ◽  
Charlotta G. Folkesson ◽  
Ole Kristensen ◽  
...  
Keyword(s):  
Small Molecule ◽  
Living Cell ◽  
Small Molecule Libraries

Functional analysis of the chemokine receptor CCR3 on purified human eosinophils

2003 ◽  
Vol 111 (2) ◽  
pp. S259
Author(s):  
J.W. Loveless ◽  
M.E. Brummet ◽  
B.S. Dailey ◽  
T.E. Nutku ◽  
C. Stellato ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Chemokine Receptor ◽  
Chemokine Receptor Ccr3
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