کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8479032 | 1551275 | 2016 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Bupropion and its photoreactive analog (±)-SADU-3-72 interact with luminal and non-luminal sites at human α4β2 nicotinic acetylcholine receptors
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کلمات کلیدی
DMEMκ-bungarotoxinNCATMDAChRAVGECDIC50RMSDFBSDulbecco's modified Eagle Medium - Eagle Medium اصلاح شده DulbeccoNoncompetitive antagonist - آنتاگونیست غیر رقابتیBupropion - بوپروپیونDissociation constant - حد تفکیکextracellular domain - دامنه خارج سلولیtransmembrane domain - دامنه فرابنفشRoom temperature - دمای اتاقMolecular dynamics - دینامیک ملکولی یا پویایی مولکولیfetal bovine serum - سرم جنین گاوHill coefficient - ضریب هیلinhibition constant - مهار ثابتroot mean square deviation - میانگین انحراف مربع ریشهCa2+ influx - نفوذ Ca2 +H-bond - پیوند HHydrogen bond - پیوند هیدروژنیMolecular docking - پیوندهای بین مولکولیVAR - که در آنnicotinic acetylcholine receptor - گیرنده استیلکولین نیکوتین
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
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چکیده انگلیسی
The interaction of (±)-bupropion [(±)-BP] with the human (h) α4β2 nicotinic acetylcholine receptor (AChR) was compared to that for its photoreactive analog (±)-2-(N-tert-butylamino)-3â²-iodo-4â²-azidopropiophenone [(±)-SADU-3-72]. Ca2+ influx results indicated that (±)-SADU-3-72 and (±)-BP inhibit hα4β2 AChRs with practically the same potency. However, (±)-SADU-3-72 binds to the [3H]imipramine sites at resting and desensitized hα4β2 AChRs with 3-fold higher affinity compared to that for (±)-BP, which is supported by molecular docking results. The docking results also indicate that each isomer of BP and SADU-3-72, in the protonated state, interacts with luminal and non-luminal sites. In the channel lumen, both ligands bind to two overlapping subsites, one that overlaps the imipramine site, and another much closer to the cytoplasmic side. The results suggest, for the first time, three differentiated non-luminal domains, including the transmembrane (TMD), extracellular (ECD), and ECD-TMD junction. In the ECD-TMD junction, BP and SADU-3-72 bind to overlapping sites. Interestingly, only SADU-3-72 binds to intrasubunit and intersubunit sites in the TMD, and to additional sites in the ECD. Our results are consistent with a model where BP and SADU-3-72 bind to overlapping sites in the luminal and ECD-TMD junctional domains of the hα4β2, whereas only SADU-3-72 binds to additional non-luminal sites. The BP junctional site opens the door for additional inhibitory mechanisms. The pharmacological properties of (±)-SADU-3-72 showed in this work support further photolabeling studies to mapping the BP binding sites in the hα4β2 AChR.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurochemistry International - Volume 100, November 2016, Pages 67-77
Journal: Neurochemistry International - Volume 100, November 2016, Pages 67-77
نویسندگان
Hugo R. Arias, Dominik Feuerbach, Marcelo O. Ortells,