Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2

Histamine receptor 2 (HR<sub<H2</sub<) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of actio...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Amisha Patel [verfasserIn] Paola L. Marquez-Gomez [verfasserIn] Lily R. Torp [verfasserIn] Lily Gao [verfasserIn] Pamela Peralta-Yahya [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	GPCRs histamine H2 receptor HR

Übergeordnetes Werk:	In: Biosensors - MDPI AG, 2012, 13(2023), 6, p 571
Übergeordnetes Werk:	volume:13 ; year:2023 ; number:6, p 571

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/bios13060571

Katalog-ID:	DOAJ094195307

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520			\|a Histamine receptor 2 (HR<sub<H2</sub<) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR<sub<H2</sub<-based sensor in yeast to evaluate the role of key residues in the HR<sub<H2</sub< active site on histamine and 8HQ-based blocker binding. We find that the HR<sub<H2</sub< mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR<sub<H2</sub<:D186A and HR<sub<H2</sub<:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR<sub<H2</sub< blockers that interact with both ends of the HR<sub<H2</sub< binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR<sub<H2</sub<:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR<sub<H2</sub< therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics.
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allfields	10.3390/bios13060571 doi (DE-627)DOAJ094195307 (DE-599)DOAJ9a9821c41c4744cebbd5ea1b48c40167 DE-627 ger DE-627 rakwb eng TP248.13-248.65 Amisha Patel verfasserin aut Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Histamine receptor 2 (HR<sub<H2</sub<) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR<sub<H2</sub<-based sensor in yeast to evaluate the role of key residues in the HR<sub<H2</sub< active site on histamine and 8HQ-based blocker binding. We find that the HR<sub<H2</sub< mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR<sub<H2</sub<:D186A and HR<sub<H2</sub<:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR<sub<H2</sub< blockers that interact with both ends of the HR<sub<H2</sub< binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR<sub<H2</sub<:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR<sub<H2</sub< therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics. GPCRs histamine H2 receptor HR<sub<H2</sub< blockers Biotechnology Paola L. Marquez-Gomez verfasserin aut Lily R. Torp verfasserin aut Lily Gao verfasserin aut Pamela Peralta-Yahya verfasserin aut In Biosensors MDPI AG, 2012 13(2023), 6, p 571 (DE-627)718626451 (DE-600)2662125-3 20796374 nnns volume:13 year:2023 number:6, p 571 https://doi.org/10.3390/bios13060571 kostenfrei https://doaj.org/article/9a9821c41c4744cebbd5ea1b48c40167 kostenfrei https://www.mdpi.com/2079-6374/13/6/571 kostenfrei https://doaj.org/toc/2079-6374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023 6, p 571
spelling	10.3390/bios13060571 doi (DE-627)DOAJ094195307 (DE-599)DOAJ9a9821c41c4744cebbd5ea1b48c40167 DE-627 ger DE-627 rakwb eng TP248.13-248.65 Amisha Patel verfasserin aut Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Histamine receptor 2 (HR<sub<H2</sub<) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR<sub<H2</sub<-based sensor in yeast to evaluate the role of key residues in the HR<sub<H2</sub< active site on histamine and 8HQ-based blocker binding. We find that the HR<sub<H2</sub< mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR<sub<H2</sub<:D186A and HR<sub<H2</sub<:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR<sub<H2</sub< blockers that interact with both ends of the HR<sub<H2</sub< binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR<sub<H2</sub<:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR<sub<H2</sub< therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics. GPCRs histamine H2 receptor HR<sub<H2</sub< blockers Biotechnology Paola L. Marquez-Gomez verfasserin aut Lily R. Torp verfasserin aut Lily Gao verfasserin aut Pamela Peralta-Yahya verfasserin aut In Biosensors MDPI AG, 2012 13(2023), 6, p 571 (DE-627)718626451 (DE-600)2662125-3 20796374 nnns volume:13 year:2023 number:6, p 571 https://doi.org/10.3390/bios13060571 kostenfrei https://doaj.org/article/9a9821c41c4744cebbd5ea1b48c40167 kostenfrei https://www.mdpi.com/2079-6374/13/6/571 kostenfrei https://doaj.org/toc/2079-6374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023 6, p 571
allfields_unstemmed	10.3390/bios13060571 doi (DE-627)DOAJ094195307 (DE-599)DOAJ9a9821c41c4744cebbd5ea1b48c40167 DE-627 ger DE-627 rakwb eng TP248.13-248.65 Amisha Patel verfasserin aut Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Histamine receptor 2 (HR<sub<H2</sub<) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR<sub<H2</sub<-based sensor in yeast to evaluate the role of key residues in the HR<sub<H2</sub< active site on histamine and 8HQ-based blocker binding. We find that the HR<sub<H2</sub< mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR<sub<H2</sub<:D186A and HR<sub<H2</sub<:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR<sub<H2</sub< blockers that interact with both ends of the HR<sub<H2</sub< binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR<sub<H2</sub<:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR<sub<H2</sub< therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics. GPCRs histamine H2 receptor HR<sub<H2</sub< blockers Biotechnology Paola L. Marquez-Gomez verfasserin aut Lily R. Torp verfasserin aut Lily Gao verfasserin aut Pamela Peralta-Yahya verfasserin aut In Biosensors MDPI AG, 2012 13(2023), 6, p 571 (DE-627)718626451 (DE-600)2662125-3 20796374 nnns volume:13 year:2023 number:6, p 571 https://doi.org/10.3390/bios13060571 kostenfrei https://doaj.org/article/9a9821c41c4744cebbd5ea1b48c40167 kostenfrei https://www.mdpi.com/2079-6374/13/6/571 kostenfrei https://doaj.org/toc/2079-6374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023 6, p 571
allfieldsGer	10.3390/bios13060571 doi (DE-627)DOAJ094195307 (DE-599)DOAJ9a9821c41c4744cebbd5ea1b48c40167 DE-627 ger DE-627 rakwb eng TP248.13-248.65 Amisha Patel verfasserin aut Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Histamine receptor 2 (HR<sub<H2</sub<) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR<sub<H2</sub<-based sensor in yeast to evaluate the role of key residues in the HR<sub<H2</sub< active site on histamine and 8HQ-based blocker binding. We find that the HR<sub<H2</sub< mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR<sub<H2</sub<:D186A and HR<sub<H2</sub<:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR<sub<H2</sub< blockers that interact with both ends of the HR<sub<H2</sub< binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR<sub<H2</sub<:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR<sub<H2</sub< therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics. GPCRs histamine H2 receptor HR<sub<H2</sub< blockers Biotechnology Paola L. Marquez-Gomez verfasserin aut Lily R. Torp verfasserin aut Lily Gao verfasserin aut Pamela Peralta-Yahya verfasserin aut In Biosensors MDPI AG, 2012 13(2023), 6, p 571 (DE-627)718626451 (DE-600)2662125-3 20796374 nnns volume:13 year:2023 number:6, p 571 https://doi.org/10.3390/bios13060571 kostenfrei https://doaj.org/article/9a9821c41c4744cebbd5ea1b48c40167 kostenfrei https://www.mdpi.com/2079-6374/13/6/571 kostenfrei https://doaj.org/toc/2079-6374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023 6, p 571
allfieldsSound	10.3390/bios13060571 doi (DE-627)DOAJ094195307 (DE-599)DOAJ9a9821c41c4744cebbd5ea1b48c40167 DE-627 ger DE-627 rakwb eng TP248.13-248.65 Amisha Patel verfasserin aut Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Histamine receptor 2 (HR<sub<H2</sub<) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR<sub<H2</sub<-based sensor in yeast to evaluate the role of key residues in the HR<sub<H2</sub< active site on histamine and 8HQ-based blocker binding. We find that the HR<sub<H2</sub< mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR<sub<H2</sub<:D186A and HR<sub<H2</sub<:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR<sub<H2</sub< blockers that interact with both ends of the HR<sub<H2</sub< binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR<sub<H2</sub<:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR<sub<H2</sub< therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics. GPCRs histamine H2 receptor HR<sub<H2</sub< blockers Biotechnology Paola L. Marquez-Gomez verfasserin aut Lily R. Torp verfasserin aut Lily Gao verfasserin aut Pamela Peralta-Yahya verfasserin aut In Biosensors MDPI AG, 2012 13(2023), 6, p 571 (DE-627)718626451 (DE-600)2662125-3 20796374 nnns volume:13 year:2023 number:6, p 571 https://doi.org/10.3390/bios13060571 kostenfrei https://doaj.org/article/9a9821c41c4744cebbd5ea1b48c40167 kostenfrei https://www.mdpi.com/2079-6374/13/6/571 kostenfrei https://doaj.org/toc/2079-6374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023 6, p 571
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callnumber-first	T - Technology
author	Amisha Patel
spellingShingle	Amisha Patel misc TP248.13-248.65 misc GPCRs misc histamine H2 receptor misc HR<sub<H2</sub< blockers misc Biotechnology Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2
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title	Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2
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title_sort	insight into the mode of action of 8-hydroxyquinoline-based blockers on the histamine receptor 2
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title_auth	Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2
abstract	Histamine receptor 2 (HR<sub<H2</sub<) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR<sub<H2</sub<-based sensor in yeast to evaluate the role of key residues in the HR<sub<H2</sub< active site on histamine and 8HQ-based blocker binding. We find that the HR<sub<H2</sub< mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR<sub<H2</sub<:D186A and HR<sub<H2</sub<:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR<sub<H2</sub< blockers that interact with both ends of the HR<sub<H2</sub< binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR<sub<H2</sub<:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR<sub<H2</sub< therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics.
abstractGer	Histamine receptor 2 (HR<sub<H2</sub<) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR<sub<H2</sub<-based sensor in yeast to evaluate the role of key residues in the HR<sub<H2</sub< active site on histamine and 8HQ-based blocker binding. We find that the HR<sub<H2</sub< mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR<sub<H2</sub<:D186A and HR<sub<H2</sub<:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR<sub<H2</sub< blockers that interact with both ends of the HR<sub<H2</sub< binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR<sub<H2</sub<:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR<sub<H2</sub< therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics.
abstract_unstemmed	Histamine receptor 2 (HR<sub<H2</sub<) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR<sub<H2</sub<-based sensor in yeast to evaluate the role of key residues in the HR<sub<H2</sub< active site on histamine and 8HQ-based blocker binding. We find that the HR<sub<H2</sub< mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR<sub<H2</sub<:D186A and HR<sub<H2</sub<:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR<sub<H2</sub< blockers that interact with both ends of the HR<sub<H2</sub< binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR<sub<H2</sub<:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR<sub<H2</sub< therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics.
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Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR<sub<H2</sub<. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR<sub<H2</sub<-based sensor in yeast to evaluate the role of key residues in the HR<sub<H2</sub< active site on histamine and 8HQ-based blocker binding. We find that the HR<sub<H2</sub< mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR<sub<H2</sub<:D186A and HR<sub<H2</sub<:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR<sub<H2</sub< blockers that interact with both ends of the HR<sub<H2</sub< binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR<sub<H2</sub<:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR<sub<H2</sub< therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">GPCRs</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">histamine H2 receptor</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">HR<sub<H2</sub< blockers</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Biotechnology</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Paola L. Marquez-Gomez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Lily R. 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