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Identification of a carbohydrate recognition motif of purinergic receptors

As a major class of biomolecules, carbohydrates play indispensable roles in various biological processes. However, it remains largely unknown how carbohydrates directly modulate important drug targets, such as G-protein coupled receptors (GPCRs). Here, we employed P2Y purinoceptor 14 (P2Y14), a drug...

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Autores principales: Zhao, Lifen, Wei, Fangyu, He, Xinheng, Dai, Antao, Yang, Dehua, Jiang, Hualiang, Wen, Liuqing, Cheng, Xi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642967/
https://www.ncbi.nlm.nih.gov/pubmed/37955640
http://dx.doi.org/10.7554/eLife.85449
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author Zhao, Lifen
Wei, Fangyu
He, Xinheng
Dai, Antao
Yang, Dehua
Jiang, Hualiang
Wen, Liuqing
Cheng, Xi
author_facet Zhao, Lifen
Wei, Fangyu
He, Xinheng
Dai, Antao
Yang, Dehua
Jiang, Hualiang
Wen, Liuqing
Cheng, Xi
author_sort Zhao, Lifen
collection PubMed
description As a major class of biomolecules, carbohydrates play indispensable roles in various biological processes. However, it remains largely unknown how carbohydrates directly modulate important drug targets, such as G-protein coupled receptors (GPCRs). Here, we employed P2Y purinoceptor 14 (P2Y14), a drug target for inflammation and immune responses, to uncover the sugar nucleotide activation of GPCRs. Integrating molecular dynamics simulation with functional study, we identified the uridine diphosphate (UDP)-sugar-binding site on P2Y14, and revealed that a UDP-glucose might activate the receptor by bridging the transmembrane (TM) helices 2 and 7. Between TM2 and TM7 of P2Y14, a conserved salt bridging chain (K(2.60)-D(2.64)-K(7.35)-E(7.36) [KDKE]) was identified to distinguish different UDP-sugars, including UDP-glucose, UDP-galactose, UDP-glucuronic acid, and UDP-N-acetylglucosamine. We identified the KDKE chain as a conserved functional motif of sugar binding for both P2Y14 and P2Y purinoceptor 12 (P2Y12), and then designed three sugar nucleotides as agonists of P2Y12. These results not only expand our understanding for activation of purinergic receptors but also provide insights for the carbohydrate drug development for GPCRs.
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spelling pubmed-106429672023-11-14 Identification of a carbohydrate recognition motif of purinergic receptors Zhao, Lifen Wei, Fangyu He, Xinheng Dai, Antao Yang, Dehua Jiang, Hualiang Wen, Liuqing Cheng, Xi eLife Computational and Systems Biology As a major class of biomolecules, carbohydrates play indispensable roles in various biological processes. However, it remains largely unknown how carbohydrates directly modulate important drug targets, such as G-protein coupled receptors (GPCRs). Here, we employed P2Y purinoceptor 14 (P2Y14), a drug target for inflammation and immune responses, to uncover the sugar nucleotide activation of GPCRs. Integrating molecular dynamics simulation with functional study, we identified the uridine diphosphate (UDP)-sugar-binding site on P2Y14, and revealed that a UDP-glucose might activate the receptor by bridging the transmembrane (TM) helices 2 and 7. Between TM2 and TM7 of P2Y14, a conserved salt bridging chain (K(2.60)-D(2.64)-K(7.35)-E(7.36) [KDKE]) was identified to distinguish different UDP-sugars, including UDP-glucose, UDP-galactose, UDP-glucuronic acid, and UDP-N-acetylglucosamine. We identified the KDKE chain as a conserved functional motif of sugar binding for both P2Y14 and P2Y purinoceptor 12 (P2Y12), and then designed three sugar nucleotides as agonists of P2Y12. These results not only expand our understanding for activation of purinergic receptors but also provide insights for the carbohydrate drug development for GPCRs. eLife Sciences Publications, Ltd 2023-11-13 /pmc/articles/PMC10642967/ /pubmed/37955640 http://dx.doi.org/10.7554/eLife.85449 Text en © 2023, Zhao et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Computational and Systems Biology
Zhao, Lifen
Wei, Fangyu
He, Xinheng
Dai, Antao
Yang, Dehua
Jiang, Hualiang
Wen, Liuqing
Cheng, Xi
Identification of a carbohydrate recognition motif of purinergic receptors
title Identification of a carbohydrate recognition motif of purinergic receptors
title_full Identification of a carbohydrate recognition motif of purinergic receptors
title_fullStr Identification of a carbohydrate recognition motif of purinergic receptors
title_full_unstemmed Identification of a carbohydrate recognition motif of purinergic receptors
title_short Identification of a carbohydrate recognition motif of purinergic receptors
title_sort identification of a carbohydrate recognition motif of purinergic receptors
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642967/
https://www.ncbi.nlm.nih.gov/pubmed/37955640
http://dx.doi.org/10.7554/eLife.85449
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