Synthesis and Application of the First Radioligand Targeting the Allosteric Binding Pocket of Chemokine Receptor CXCR3

ChemMedChem ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. 1481-1489 ◽  
Author(s):  
Viachaslau Bernat ◽  
Markus R. Heinrich ◽  
Paul Baumeister ◽  
Armin Buschauer ◽  
Nuska Tschammer
Keyword(s):  
Chemokine Receptor ◽  
Binding Pocket ◽  
Allosteric Binding Pocket

Structure-based exploration of an allosteric binding pocket in the NTS1 receptor using bitopic NT(8-13) derivatives and molecular dynamics simulations

2019 ◽  
Vol 25 (7) ◽  
Author(s):  
Ralf Christian Kling ◽  
Carolin Burchardt ◽  
Jürgen Einsiedel ◽  
Harald Hübner ◽  
Peter Gmeiner
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Pocket ◽  
Dynamics Simulations ◽  
Allosteric Binding Pocket

Highly Selective Y4 Receptor Antagonist Binds in an Allosteric Binding Pocket

2021 ◽  
Vol 64 (5) ◽  
pp. 2801-2814
Author(s):  
Corinna Schüß ◽  
Oanh Vu ◽  
Mario Schubert ◽  
Yu Du ◽  
Nigam M. Mishra ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Binding Pocket ◽  
Allosteric Binding Pocket ◽  
Y4 Receptor

scholarly journals Characterization of the allosteric binding pocket of human liver fructose-1,6-bisphosphatase by protein crystallography and inhibitor activity studies

1997 ◽  
Vol 6 (5) ◽  
pp. 971-982 ◽  
Author(s):  
L. F. Iversen ◽  
M. Brzozowski ◽  
S. Hastrup ◽  
R. Hubbard ◽  
J. S. Kastrup ◽  
...  
Keyword(s):  
Human Liver ◽  
Protein Crystallography ◽  
Binding Pocket ◽  
Inhibitor Activity ◽  
Fructose 1,6 Bisphosphatase ◽  
Allosteric Binding Pocket

Hindered nucleoside analogs as antiflaviviridae agents

2004 ◽  
Vol 76 (5) ◽  
pp. 1007-1015 ◽  
Author(s):  
Stefano Manfredini ◽  
Angela Angusti ◽  
A. C. Veronese ◽  
Elisa Durini ◽  
S. Vertuani ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Molecular Modeling ◽  
Rna Polymerase ◽  
Nucleoside Analogs ◽  
Binding Pocket ◽  
West Nile Fever ◽  
Rna Dependent Rna Polymerase ◽  
West Nile ◽  
Important Family ◽  
Allosteric Binding Pocket

Flaviviridae are an important family of viruses, responsible for widely spread diseases such as dengue and West Nile fever and hepatitis C. Despite the severity of the related diseases, no effective antiviral treatments for infection are available. Following our discovery of adenosine-hindered analogs as potent antiflaviviridae agents, we have continued our investigation on guanosine and inosine derivatives, which were evaluated for activity against BVDV, YFV, DENV, and WNV viruses in cell-based assays. The present study allowed us to identify some newer features that led to improve the antiviral potency (down to the µM range) and to selectively inhibit BVDV and YFV viruses. The molecular modeling results were consistent with the hypothesis that test analogs act as RNA-dependent RNA polymerase (RdRp) inhibitors by interacting with a surface allosteric binding pocket.

scholarly journals Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists

2013 ◽  
Vol 41 (1) ◽  
pp. 213-217 ◽  
Author(s):  
Inna Hoyer ◽  
Ann-Karin Haas ◽  
Annika Kreuchwig ◽  
Ralf Schülein ◽  
Gerd Krause
Keyword(s):  
Amino Acids ◽  
Structural Model ◽  
Transmembrane Domain ◽  
Binding Pocket ◽  
Trigger Points ◽  
Antagonistic Effect ◽  
Site Directed Mutagenesis ◽  
Detailed Knowledge ◽  
Contact Points ◽  
Allosteric Binding Pocket

The TSHR (thyrotropin receptor) is activated endogenously by the large hormone thyrotropin and activated pathologically by auto-antibodies. Both activate and bind at the extracellular domain. Recently, SMLs (small-molecule ligands) have been identified, which bind in an allosteric binding pocket within the transmembrane domain. Modelling driven site-directed mutagenesis of amino acids lining this pocket led to the delineation of activation and inactivation sensitive residues. Modified residues showing CAMs (constitutively activating mutations) indicate signalling-sensitive positions and mark potential trigger points for agonists. Silencing mutations lead to an impairment of basal activity and mark contact points for antagonists. Mapping these residues on to a structural model of TSHR indicates locations where an SML may switch the receptor to an inactive or active conformation. In the present article, we report the effects of SMLs on these signalling-sensitive amino acids at the TSHR. Surprisingly, the antagonistic effect of SML compound 52 was reversed to an agonistic effect, when tested at the CAM Y667A. Switching agonism to antagonism and the reverse by changing either SMLs or residues covering the binding pocket provides detailed knowledge about discriminative pharmacophores. It prepares the basis for rational optimization of new high-affinity antagonists to interfere with the pathogenic activation of the TSHR.

scholarly journals Structural basis for ligand modulation of the CCR2 conformational landscape

2018 ◽  
Author(s):  
Bryn C. Taylor ◽  
Christopher T. Lee ◽  
Rommie E. Amaro
Keyword(s):  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Drug Targets ◽  
Control Cell ◽  
Binding Pocket ◽  
Drug Binding ◽  
Structural Basis ◽  
Cc Chemokine ◽  
Wide Range ◽  
Dynamics Simulations

AbstractCC Chemokine Receptor 2 (CCR2) is a part of the chemokine receptor family, an important class of therapeutic targets. These class A G-protein coupled receptors (GPCRs) are involved in mammalian signaling pathways and control cell migration toward endogenous CC chemokine ligands. Chemokine receptors and their associated ligands are involved in a wide range of diseases and thus have become important drug targets. Of particular interest is CCR2, which has been implicated in cancer, autoimmunity driven type-1 diabetes, diabetic nephropathy, multiple sclerosis, asthma, atherosclerosis, neuropathic pain, and rheumatoid arthritis. Although promising, CCR2 antagonists have been largely unsuccessful to date. Here, we investigate the effect of an orthosteric and an allosteric antagonist on CCR2 dynamics by coupling long timescale molecular dynamics simulations with Markov-state model theory. We find that the antagonists shift CCR2 into several stable inactive conformations that are distinct from the crystal structure conformation, and that they disrupt a continuous internal water and sodium ion pathway preventing transitions to an active-like state. Several of these stable conformations contain a putative drug binding pocket that may be amenable to targeting with another small molecule antagonist. In the absence of antagonists, the apo dynamics reveal intermediate conformations along the activation pathway that provide insight into the basal dynamics of CCR2, and may also be useful for future drug design.

scholarly journals Structural basis for ligand modulation of the CCR2 conformational landscape

2019 ◽  
Vol 116 (17) ◽  
pp. 8131-8136 ◽  
Author(s):  
Bryn C. Taylor ◽  
Christopher T. Lee ◽  
Rommie E. Amaro
Keyword(s):  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Drug Targets ◽  
Control Cell ◽  
Binding Pocket ◽  
Drug Binding ◽  
Structural Basis ◽  
Allosteric Site ◽  
Cc Chemokine ◽  
Wide Range

CC chemokine receptor 2 (CCR2) is a part of the chemokine receptor family, an important class of therapeutic targets. These class A G-protein coupled receptors (GPCRs) are involved in mammalian signaling pathways and control cell migration toward endogenous CC chemokine ligands, named for the adjacent cysteine motif on their N terminus. Chemokine receptors and their associated ligands are involved in a wide range of diseases and thus have become important drug targets. CCR2, in particular, promotes the metastasis of cancer cells and is also implicated in autoimmunity-driven type-1 diabetes, diabetic nephropathy, multiple sclerosis, asthma, atherosclerosis, neuropathic pain, and rheumatoid arthritis. Although promising, CCR2 antagonists have been largely unsuccessful to date. Here, we investigate the effect of an orthosteric and an allosteric antagonist on CCR2 dynamics by coupling long-timescale molecular dynamics simulations with Markov-state model theory. We find that the antagonists shift CCR2 into several stable inactive conformations that are distinct from the crystal structure conformation and disrupt a continuous internal water and sodium ion pathway, preventing transitions to an active-like state. Several metastable conformations present a cryptic drug-binding pocket near the allosteric site that may be amenable to targeting with small molecules. Without antagonists, the apo dynamics reveal intermediate conformations along the activation pathway that provide insight into the basal dynamics of CCR2 and may also be useful for future drug design.

scholarly journals Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Rebecca C. Allsopp ◽  
Sudad Dayl ◽  
Ralf Schmid ◽  
Richard J. Evans
Keyword(s):  
P2x7 Receptor ◽  
Binding Pocket ◽  
Selective Antagonist ◽  
Allosteric Binding Pocket

scholarly journals Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1

2021 ◽  
Author(s):  
Zhehua Shao ◽  
Qingya Shen ◽  
Bingpeng Yao ◽  
Chunyou Mao ◽  
Li-Nan Chen ◽  
...  
Keyword(s):  
G Protein ◽  
Chemokine Receptor ◽  
Binding Pocket ◽  
Structural Basis ◽  
Free Form ◽  
Downstream Signaling ◽  
Receptor Complexes ◽  
Ligand Free ◽  
Biased Signaling ◽  
G Protein Coupled

AbstractBiased signaling of G protein-coupled receptors describes an ability of different ligands that preferentially activate an alternative downstream signaling pathway. In this work, we identified and characterized different N-terminal truncations of endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, and presented three cryogenic-electron microscopy structures of the CCR1–Gi complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6–2.9 Å, illustrating the structural basis of natural biased signaling that initiates an inflammation response. Complemented with pharmacological and computational studies, these structures revealed it was the conformational change of Tyr291 (Y2917.43) in CCR1 that triggered its polar network rearrangement in the orthosteric binding pocket and allosterically regulated the activation of β-arrestin signaling. Our structure of CCL15-bound CCR1 also exhibited a critical site for ligand binding distinct from many other chemokine–receptor complexes, providing new insights into the mode of chemokine recognition.

scholarly journals CXCL10 Is an Agonist of the CC Family Chemokine Scavenger Receptor ACKR2/D6

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1054
Author(s):  
Andy Chevigné ◽  
Bassam Janji ◽  
Max Meyrath ◽  
Nathan Reynders ◽  
Giulia D’Uonnolo ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Scavenger Receptor ◽  
Binding Pocket ◽  
Tumour Immunology ◽  
Dipeptidyl Peptidase 4 ◽  
Highly Sensitive ◽  
Inflammatory Chemokines ◽  
Cc Chemokines

Atypical chemokine receptors (ACKRs) are important regulators of chemokine functions. Among them, the atypical chemokine receptor ACKR2 (also known as D6) has long been considered as a scavenger of inflammatory chemokines exclusively from the CC family. In this study, by using highly sensitive β-arrestin recruitment assays based on NanoBiT and NanoBRET technologies, we identified the inflammatory CXC chemokine CXCL10 as a new strong agonist ligand for ACKR2. CXCL10 is known to play an important role in the infiltration of immune cells into the tumour bed and was previously reported to bind to CXCR3 only. We demonstrated that ACKR2 is able to internalize and reduce the availability of CXCL10 in the extracellular space. Moreover, we found that, in contrast to CC chemokines, CXCL10 activity towards ACKR2 was drastically reduced by the dipeptidyl peptidase 4 (DPP4 or CD26) N-terminal processing, pointing to a different receptor binding pocket occupancy by CC and CXC chemokines. Overall, our study sheds new light on the complexity of the chemokine network and the potential role of CXCL10 regulation by ACKR2 in many physiological and pathological processes, including tumour immunology. Our data also testify that systematic reassessment of chemokine-receptor pairing is critically needed as important interactions may remain unexplored.

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