دورية أكاديمية
أعرض في EDS

Identification of a carbohydrate recognition motif of purinergic receptors.

التفاصيل البيبلوغرافية
العنوان: Identification of a carbohydrate recognition motif of purinergic receptors.
المؤلفون: Zhao L; State Key Laboratory of Drug Research, Carbohydrate-Based Drug Research Center and National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., Wei F; State Key Laboratory of Drug Research, Carbohydrate-Based Drug Research Center and National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China., He X; State Key Laboratory of Drug Research, Carbohydrate-Based Drug Research Center and National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China., Dai A; State Key Laboratory of Drug Research, Carbohydrate-Based Drug Research Center and National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., Yang D; State Key Laboratory of Drug Research, Carbohydrate-Based Drug Research Center and National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China., Jiang H; State Key Laboratory of Drug Research, Carbohydrate-Based Drug Research Center and National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China.; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou, China., Wen L; State Key Laboratory of Drug Research, Carbohydrate-Based Drug Research Center and National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China., Cheng X; State Key Laboratory of Drug Research, Carbohydrate-Based Drug Research Center and National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China.; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou, China.
المصدر: ELife [Elife] 2023 Nov 13; Vol. 12. Date of Electronic Publication: 2023 Nov 13.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
مواضيع طبية MeSH: Receptors, Purinergic* , Nucleotides*, Uridine Diphosphate Glucose ; Sugars ; Receptors, Purinergic P2Y
مستخلص: 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.
Competing Interests: LZ, FW, XH, AD, DY, HJ, LW, XC No competing interests declared
(© 2023, Zhao et al.)
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فهرسة مساهمة: Keywords: G-protein coupled receptor; computational biology; functional motif; human; recogonition mechanism; sugar nucleotide; systems biology
Local Abstract: [plain-language-summary] Sugars and other types of carbohydrates are biomolecules which play a range of key roles in the body. In particular, they are important messengers that help to coordinate immune responses. For example, a carbohydrate known as UDP-Glucose (a kind of UDP-sugar) can activate P2Y14, a receptor studded through the surface of many cells; this event then triggers a cascade of molecular events associated with asthma, kidney injury and lung inflammation. Yet it remains unclear how exactly UDP-Glucose recognizes P2Y14 – and, more broadly, how carbohydrates interact with purinergic receptors, the class of proteins that P2Y14 belongs to. To examine this question, Zhao et al. combined functional experiments in the laboratory with molecular dynamics simulations, a computational approach. This work revealed that UDP-Glucose may activate P2Y14 by bridging its segments anchored within the cell membrane. A component of P2Y14, known as the KDKE chain, was found to have an important role in distinguishing between highly similar types of UDP-sugars. This allowed Zhao et al. to design three sugar molecules which could activate another purinergic receptor that also contained a KDKE chain. Purinergic receptors are promising therapeutic targets. A finer understanding of how they recognise the molecules that activate them is therefore important to be able to identify and design new drug compounds.
المشرفين على المادة: 0 (Receptors, Purinergic)
0 (Nucleotides)
V50K1D7P4Y (Uridine Diphosphate Glucose)
0 (Sugars)
0 (Receptors, Purinergic P2Y)
تواريخ الأحداث: Date Created: 20231113 Date Completed: 20231114 Latest Revision: 20231115
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC10642967
DOI: 10.7554/eLife.85449
PMID: 37955640
قاعدة البيانات: MEDLINE
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.85449