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药物研发中的荧光相关光谱法：研究Alexa532标记的内皮素-1与内皮素ETA受体的结合，以描述天然产物的药理学特征。

Fluorescence correlation spectroscopy in drug discovery: study of Alexa532-endothelin 1 binding to the endothelin ETA receptor to describe the pharmacological profile of natural products.

作者信息

Caballero-George Catherina, Sorkalla Thomas, Jakobs Daniel, Bolaños Jessica, Raja Huzefa, Shearer Carol, Bermingham Eldredge, Häberlein Hanns

机构信息

Department of Molecular Pharmacology and Pharmacognosy, Drug Discovery Center, Institute for Scientific Research and High Technology Services, Panama City, Panama.

出版信息

ScientificWorldJournal. 2012;2012:524169. doi: 10.1100/2012/524169. Epub 2012 May 1.

DOI:10.1100/2012/524169
PMID:22623909
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3353486/
Abstract

Fluorescence correlation spectroscopy and the newly synthesized Alexa532-ET1 were used to study the dynamics of the endothelin ET(A) receptor-ligand complex alone and under the influence of a semisynthetic selective antagonist and a fungal extract on living A10 cells. Dose-dependent increase of inositol phosphate production was seen for Alexa532-ET1, and its binding was reduced to 8% by the selective endothelin ET(A) antagonist BQ-123, confirming the specific binding of Alexa532-ET1 to the endothelin ET(A) receptor. Two different lateral mobilities of the receptor-ligand complexes within the cell membrane were found allowing the discrimination of different states for this complex. BQ-123 showed a strong binding affinity to the "inactive" receptor state characterized by the slow diffusion time constant. A similar effect was observed for the fungal extract, which completely displaced Alexa532-ET1 from its binding to the "inactive" receptor state. These findings suggest that both BQ-123 and the fungal extract act as inverse agonists.

摘要

利用荧光相关光谱法和新合成的Alexa532 - ET1研究了内皮素ET(A)受体 - 配体复合物在单独情况下以及在半合成选择性拮抗剂和真菌提取物作用下于活A10细胞中的动力学。Alexa532 - ET1可使肌醇磷酸生成呈剂量依赖性增加，其结合被选择性内皮素ET(A)拮抗剂BQ - 123降低至8%，证实了Alexa532 - ET1与内皮素ET(A)受体的特异性结合。发现细胞膜内受体 - 配体复合物存在两种不同的横向迁移率，这使得能够区分该复合物的不同状态。BQ - 123对以慢扩散时间常数为特征的“无活性”受体状态表现出强烈的结合亲和力。真菌提取物也观察到类似效果，它能使Alexa532 - ET1完全从其与“无活性”受体状态的结合中被取代。这些发现表明BQ - 123和真菌提取物均作为反向激动剂起作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6501/3353486/1f92f812c833/TSWJ2012-524169.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6501/3353486/0065168bcaee/TSWJ2012-524169.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6501/3353486/a2b6f901cc8f/TSWJ2012-524169.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6501/3353486/7d7d458f1f72/TSWJ2012-524169.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6501/3353486/1f92f812c833/TSWJ2012-524169.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6501/3353486/0065168bcaee/TSWJ2012-524169.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6501/3353486/a2b6f901cc8f/TSWJ2012-524169.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6501/3353486/7d7d458f1f72/TSWJ2012-524169.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6501/3353486/1f92f812c833/TSWJ2012-524169.004.jpg

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