Structural insight into allosteric modulation of protease-activated receptor 2
Crystal structures of protease-activated receptor 2 (PAR2) in complex with two different antagonist ligands and with a blocking antibody reveal binding sites that are distinct from those found on PAR1, offering new leads for structure-based drug design. PAR2 structures shed light on allosteric mecha...
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| Veröffentlicht in: | Nature (London) Jg. 545; H. 7652; S. 112 - 115 |
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
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London
Nature Publishing Group UK
04.05.2017
Nature Publishing Group |
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| ISSN: | 0028-0836, 1476-4687, 1476-4687 |
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| Abstract | Crystal structures of protease-activated receptor 2 (PAR2) in complex with two different antagonist ligands and with a blocking antibody reveal binding sites that are distinct from those found on PAR1, offering new leads for structure-based drug design.
PAR2 structures shed light on allosteric mechanisms
Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) with roles in diverse diseases, such as neuroinflammation and cancer, and are considered important target for drug discovery. Here, Fiona Marshall and colleagues have determined three crystal structures of PAR2 in complex with two different antagonists and a blocking antibody, respectively. The antagonists bind to distinct allosteric sites on the receptor and these binding sites are different to the one previously found on PAR1. Therefore this family of GPCRs can be inhibited by a number of different allosteric mechanisms, offering new leads for structure-based drug design.
Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation
1
,
2
,
3
. PARs have been the subject of major pharmaceutical research efforts
3
but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar
4
, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously
5
. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist
6
. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses. |
|---|---|
| AbstractList | Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation1-3. PARs have been the subject of major pharmaceutical research efforts3 but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar4, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously5. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist6. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses. Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses.Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses. Crystal structures of protease-activated receptor 2 (PAR2) in complex with two different antagonist ligands and with a blocking antibody reveal binding sites that are distinct from those found on PAR1, offering new leads for structure-based drug design. PAR2 structures shed light on allosteric mechanisms Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) with roles in diverse diseases, such as neuroinflammation and cancer, and are considered important target for drug discovery. Here, Fiona Marshall and colleagues have determined three crystal structures of PAR2 in complex with two different antagonists and a blocking antibody, respectively. The antagonists bind to distinct allosteric sites on the receptor and these binding sites are different to the one previously found on PAR1. Therefore this family of GPCRs can be inhibited by a number of different allosteric mechanisms, offering new leads for structure-based drug design. Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation 1 , 2 , 3 . PARs have been the subject of major pharmaceutical research efforts 3 but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar 4 , a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously 5 . Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist 6 . Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses. Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses. |
| Audience | Academic |
| Author | Brown, Giles A. Schlenker, Oliver Cheng, Robert K. Y. Doré, Andrew S. Wiggin, Giselle Brown, Dean G. Rappas, Mathieu Geschwindner, Stefan Hermansson, Nils-Olov Johansson, Patrik Thornton, Peter Tehan, Benjamin Troast, Dawn Prihandoko, Rudi Sundström, Linda Marshall, Fiona H. Edman, Karl Aggeler, Birte Snijder, Arjan Dekker, Niek Soutter, Holly Jazayeri, Ali Cooke, Robert M. Leong, Louis Dumelin, Christoph E. Fiez-Vandal, Cédric Grebner, Christoph Zhukov, Andrei |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28445455$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 2017 COPYRIGHT 2017 Nature Publishing Group Copyright Nature Publishing Group May 4, 2017 |
| Copyright_xml | – notice: Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 2017 – notice: COPYRIGHT 2017 Nature Publishing Group – notice: Copyright Nature Publishing Group May 4, 2017 |
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| DOI | 10.1038/nature22309 |
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| Snippet | Crystal structures of protease-activated receptor 2 (PAR2) in complex with two different antagonist ligands and with a blocking antibody reveal binding sites... Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N... |
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| SubjectTerms | 101/1 631/154/436/2387 631/535/1266 631/92/436 98 Allosteric properties Allosteric proteins Allosteric Regulation - drug effects Allosteric Site - drug effects Antagonist drugs Antagonists Antibodies Antibodies, Blocking - chemistry Antibodies, Blocking - pharmacology Antigens Benzimidazoles - chemistry Benzimidazoles - pharmacology Benzodioxoles - chemistry Benzodioxoles - pharmacology Benzyl Alcohols - chemistry Benzyl Alcohols - pharmacology Binding sites Blocking antibodies Cell receptors Crystal structure Crystallography, X-Ray G protein-coupled receptors Homology Humanities and Social Sciences Humans Imidazoles - chemistry Imidazoles - pharmacology Immunoglobulin Fab Fragments - chemistry Immunoglobulin Fab Fragments - pharmacology Inflammation Isoforms Kinetics letter Ligands Models, Molecular Molecular structure multidisciplinary Mutation Peptides Physiological aspects Protease Proteins Proteolysis Receptor mechanisms Receptor, PAR-2 - antagonists & inhibitors Receptor, PAR-2 - chemistry Receptor, PAR-2 - metabolism Receptors Science Signal Transduction - drug effects Thromboembolism Thrombosis |
| Title | Structural insight into allosteric modulation of protease-activated receptor 2 |
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