Structural Analysis of Chemokine Receptor–Ligand Interactions

Arimont, Marta; Sun, Shan-Liang; Leurs, Rob; Smit, Martine J.; Esch, Iwan J. P. de; Graaf, Chris de

doi:10.1021/acs.jmedchem.6b01309

Cited by 104 publications

(126 citation statements)

References 255 publications

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“…The main difference, and an intriguing finding of our study, consists in the polar interaction of the E291 7.39 side chain with the secondary amine of MK-0812. E 7.39 is present in most chemokine receptors and several mutation studies in literature have shown that this residue is important for small-molecule ligand binding to CXCR4, CCR5, CCR2, and US28 (Arimont et al, 2017). In CXCR4 (Wu et al, 2010) and CCR5 structures (Tan et al, 2013b) the corresponding residues E288 7.39 and E283 7.39 are involved in hydrogen bond and ionic interactions with the co-crystallized ligands.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of CC Chemokine Receptor 2A in Complex with an Orthosteric Antagonist Provides Insights for the Design of Selective Antagonists

Apel

Cheng²,

Tautermann

et al. 2019

Structure

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Graphical AbstractHighlights d Two CCR2A structures in complex with the orthosteric antagonist MK-0812 were solved d IMISX in situ plates facilitated high-quality diffraction data collection d Residue E291 7.39 was confirmed as important in orthosteric antagonist binding d The non-conserved residue H121 3.33 is important for CCR2 selectivity over CCR5 SUMMARYWe determined two crystal structures of the chemokine receptor CCR2A in complex with the orthosteric antagonist MK-0812. Full-length CCR2A, stabilized by rubredoxin and a series of five mutations were resolved at 3.3 Å . An N-and C-terminally truncated CCR2A construct was crystallized in an alternate crystal form, which yielded a 2.7 Å resolution structure using serial synchrotron crystallography. Our structures provide a clear structural explanation for the observed key role of residue E291 7.39 in highaffinity binding of several orthosteric CCR2 antagonists. By combining all the structural information collected, we generated models of co-structures for the structurally diverse pyrimidine amide class of CCR2 antagonists. Even though the representative Ex15 overlays well with MK-0812, it also interacts with the non-conserved H121 3.33 , resulting in a significant selectivity over CCR5. Insights derived from this work will facilitate drug discovery efforts directed toward highly selective CCR2 antagonists with potentially superior efficacy.

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Section: Discussionmentioning

confidence: 99%

Crystal Structure of CC Chemokine Receptor 2A in Complex with an Orthosteric Antagonist Provides Insights for the Design of Selective Antagonists

Apel

Cheng²,

Tautermann

et al. 2019

Structure

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“…All cytokines perform their biological functions upon binding to their transmembrane receptors. These transmembrane receptors are divided into six types according to their structure (Arimont et al 2017;Grötzinger 2002) and include type I and type II cytokine receptors, the immunoglobin superfamily of receptors, the TNF receptor family, chemokine receptors, and TGF-␤ receptors.…”

Section: Generation Of Pro-inflammatory Cytokinesmentioning

confidence: 99%

Mechanisms for the transition from physiological to pathological cardiac hypertrophy

Oldfield

Duhamel

Dhalla

2020

Can. J. Physiol. Pharmacol.

115

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The heart is capable of responding to stressful situations by increasing muscle mass, which is broadly defined as cardiac hypertrophy. This phenomenon minimizes ventricular wall stress for the heart undergoing a greater than normal workload. At initial stages, cardiac hypertrophy is associated with normal or enhanced cardiac function and is considered to be adaptive or physiological; however, at later stages, if the stimulus is not removed, it is associated with contractile dysfunction and is termed as pathological cardiac hypertrophy. It is during physiological cardiac hypertrophy where the function of subcellular organelles, including the sarcolemma, sarcoplasmic reticulum, mitochondria, and myofibrils, may be upregulated, while pathological cardiac hypertrophy is associated with downregulation of these subcellular activities. The transition of physiological cardiac hypertrophy to pathological cardiac hypertrophy may be due to the reduction in blood supply to hypertrophied myocardium as a consequence of reduced capillary density. Oxidative stress, inflammatory processes, Ca 2+ -handling abnormalities, and apoptosis in cardiomyocytes are suggested to play a critical role in the depression of contractile function during the development of pathological hypertrophy.Key words: cardiac hypertrophy, cardiac remodeling, pathological cardiac hypertrophy, physiological cardiac hypertrophy, adaptive cardiac hypertrophy, cardiac contractile function.Résumé : Le coeur est capable de réagir à des situations de stress par une augmentation de sa masse musculaire, que l'on caractérise plus largement comme étant de l'hypertrophie cardiaque. Ce phénomène permet de réduire au minimum la tension de la paroi ventriculaire dans un coeur soumis à une charge de travail plus élevée que normalement. Aux premiers stades, l'hypertrophie cardiaque est associée avec une fonction cardiaque normale ou améliorée et est considérée comme étant adaptative ou physiologique; toutefois, à des stades plus tardifs, si le stimulus n'est pas écarté, elle est associée avec un dysfonctionnement contractile et alors nommée hypertrophie cardiaque pathologique. C'est pendant l'hypertrophie cardiaque physiologique que le fonctionnement des organites sous-cellulaires, y compris le sarcolemme, le réticulum sarcoplasmique, les mitochondries et les myofibrilles peut être régulé à la hausse, tandis que l'hypertrophie cardiaque pathologique est associée avec une régulation à la baisse de ces activités sous-cellulaires. La transition de l'hypertrophie cardiaque physiologique vers l'hypertrophie cardiaque pathologique pourrait être le fait d'une diminution de l'apport sanguin au myocarde hypertrophié comme conséquence de la diminution de la densité des capillaires. On laisse entendre que le stress oxydatif, les processus inflammatoires, les anomalies de la gestion des ions Ca 2+ dans les cardiomyocytes ainsi que l'apoptose joueraient des rôles critiques dans la dépression de la fonction contractile au cours du développement de l'hypertrophie pathologique. [Traduit par...

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“…include a particular helix positioning where the top of TM2 is tilted owing to the presence of the T 2.56 xP 2.58 motif, a feature that is shared with other protein and peptide receptors (e.g., opioid receptors); a highly conserved disulfide bridge between the N-terminus and ECL3; the open, solvent-accessible 7TM domain; and a diversity of druggable pockets, in line with the chemical diversity among chemokine receptor ligands (Arimont et al, 2017).…”

Section: Structural Determinants Of Chemokine Receptor Ligand Bindingmentioning

confidence: 99%

Modulators of CXCR4 and CXCR7/ACKR3 Function

et al. 2019

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The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for human immunodeficiency virus (HIV) infection, cancer, and inflammation diseases. CXCR4 is one of only three chemokine receptors with a US Food and Drug Administration approved therapeutic agent, the smallmolecule modulator AMD3100. In this review, known modulators of the two receptors are discussed in detail. Initially, the structural relationship between receptors and ligands is reviewed on the basis of common structural motifs and available crystal structures. To date, no atypical chemokine receptor has been crystallized, which makes ligand design and predictions for these receptors more difficult. Next, the selectivity, receptor activation, and the resulting ligand-induced signaling output of chemokines and other peptide ligands are reviewed. Binding of pepducins, a class of lipid-peptides whose basis is the internal loop of a GPCR, to CXCR4 is also discussed. Finally, small-molecule modulators of CXCR4 and ACKR3 are reviewed. These modulators have led to the development of radio-and fluorescently labeled tool compounds, enabling the visualization of ligand binding and receptor characterization both in vitro and in vivo. SIGNIFICANCE STATEMENTTo investigate the pharmacological modulation of CXCR4 and ACKR3, significant effort has been focused on the discovery and development of a range of ligands, including small-molecule modulators, pepducins, and synthetic peptides. Imaging tools, such as fluorescent probes, also play a pivotal role in the field of drug discovery. This review aims to provide an overview of the aforementioned modulators that facilitate the study of CXCR4 and ACKR3 receptors.

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Structural Analysis of Chemokine Receptor–Ligand Interactions

Cited by 104 publications

References 255 publications

Crystal Structure of CC Chemokine Receptor 2A in Complex with an Orthosteric Antagonist Provides Insights for the Design of Selective Antagonists

Crystal Structure of CC Chemokine Receptor 2A in Complex with an Orthosteric Antagonist Provides Insights for the Design of Selective Antagonists

Mechanisms for the transition from physiological to pathological cardiac hypertrophy

Modulators of CXCR4 and CXCR7/ACKR3 Function

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