GPCR drug discovery-moving beyond the orthosteric to the allosteric domain

Felder, Christian C.

doi:10.1016/bs.apha.2019.04.002

Cited by 20 publications

(17 citation statements)

References 52 publications

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“…Allosteric modulation by PAMs that bind anywhere distinct from the orthosteric site of endogenous ligands and enhance the activity of agonists in an uncompetitive way is an alternative approach to peptide therapy 19 – 22 . Previous studies showed that several PAMs of GLP-1R, such as the most characterized electrophilic chemotype compound BETP 23 , 24 and the substituted quinoxaline compound 2 (6,7-dichloro-3-methanesulfonyl-2-tert-butylamino-quinoxaline) 25 , 26 , were able to initiate or promote receptor activation 9 , 27 .…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

Cong

Chen

et al. 2021

Nat Commun

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The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.

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Section: Introductionmentioning

confidence: 99%

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

Cong

Chen

et al. 2021

Nat Commun

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show abstract

“…Allosteric modulation by PAMs that bind anywhere distinct from the orthosteric site of endogenous ligands and enhance the activity of agonist in an uncompetitive way is an alternative approach to peptide therapy 19–22 . Previous studies showed that several PAMs of GLP-1R, such as the most characterized electrophilic chemotypes-compound BETP 23,24 and the substituted quinoxalines compound 2 (6,7-dichloro-3-methanesulfonyl-2-tert-butylamino-quinoxaline) 25,26 , were able to initiate or promote receptor activation 9,27 .…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

Cong

Chen

et al. 2021

Preprint

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The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer the structural basis of ago-allosterism at GLP-1R and new knowledge to design better therapeutics.

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“…1 The vast majority of the reported GPCR ligands bind to an orthosteric site located within the helical bundle, facing the extracellular side of the receptor. 2 Apart from the orthosteric site binding the endogenous ligand, an intracellular allosteric binding site (IABS) has been recently identified by X-ray cocrystallography for the chemokine receptors CCR2, 3 CXCR2, 4 CCR7, 5 CCR9, 6 as well as for the β-2 adrenergic receptor (β 2 AR). 7 Moreover, a druggable IABS has been suggested for several other GPCRs.…”

mentioning

confidence: 99%

“…G protein-coupled receptors (GPCRs) are pharmaceutically highly relevant, as they are targeted by approximately one-third of all available medications . The vast majority of the reported GPCR ligands bind to an orthosteric site located within the helical bundle, facing the extracellular side of the receptor . Apart from the orthosteric site binding the endogenous ligand, an intracellular allosteric binding site (IABS) has been recently identified by X-ray cocrystallography for the chemokine receptors CCR2, CXCR2, CCR7, CCR9, as well as for the β-2 adrenergic receptor (β 2 AR) .…”

mentioning

confidence: 99%

Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR2

et al. 2022

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Fluorescently labeled ligands are versatile molecular tools to study G protein-coupled receptors (GPCRs) and can be used for a range of different applications, including bioluminescence resonance energy transfer (BRET) assays. Here, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of the CC chemokine receptor 2 (CCR2), a class A GPCR that has been pursued as a drug target in oncology and inflammation. Starting from previously reported intracellular CCR2 antagonists, several tetramethylrhodamine (TAMRA)-labeled CCR2 ligands were designed, synthesized, and tested for their suitability as fluorescent reporters to probe binding to the IABS of CCR2. By means of these studies, we developed 14 as a fluorescent CCR2 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a non-isotopic and high-throughput manner. Further, we show that 14 can be used as a tool for fragment-based screening approaches. Thus, our small-molecule-based fluorescent CCR2 ligand 14 represents a promising tool for future studies of CCR2 pharmacology.

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GPCR drug discovery-moving beyond the orthosteric to the allosteric domain

Cited by 20 publications

References 52 publications

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR2

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