دورية أكاديمية
The molecular basis of drug selectivity for α5 subunit-containing GABAA receptors.
| العنوان: | The molecular basis of drug selectivity for α5 subunit-containing GABAA receptors. |
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| المؤلفون: | Kasaragod, Vikram Babu, Malinauskas, Tomas, Wahid, Ayla A, Lengyel, Judith, Knoflach, Frederic, Hardwick, Steven W, Jones, Charlotte F, Chen, Wan-Na, Lucas, Xavier, El Omari, Kamel, Chirgadze, Dimitri Y, Aricescu, A Radu, Cecere, Giuseppe, Hernandez, Maria-Clemencia, Miller, Paul S |
| بيانات النشر: | Springer Science and Business Media LLC //dx.doi.org/10.1038/s41594-023-01133-1 Nat Struct Mol Biol |
| سنة النشر: | 2023 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Receptors, GABA-A, gamma-Aminobutyric Acid, Isoxazoles |
| الوصف: | Acknowledgements: We acknowledge L. Cooper for training in cryo-EM grid preparation and for performing grid clipping; J. Stayaert (Vrije Universiteit Brussel) for kindly providing MbF3; M. Reutlinger and J. Benz for scientific discussions early in the project; V. Graf for electrophysiology support; and M. Karg, M. Fogetta and M. Siegrist for molecular biology support. This work was supported by a BBSRC project grant, BB/M024709/1 (P.S.M.), the Department of Pharmacology new lab start-up fund, and the University of Cambridge Isaac Newton & Wellcome Trust Institutional Strategic Support Fund, Academy of Medical Sciences Springboard Award, SBF004\1074 (P.S.M.), and funding from F. Hoffmann-La Roche Ltd. The cryo-EM facility receives funding from the Wellcome Trust, 206171/Z/17/Z; 202905/Z/16/Z (S.W.H. and D.Y.C.) and University of Cambridge. ; α5 subunit-containing γ-aminobutyric acid type A (GABAA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the α5 subunit. These define the molecular basis of binding and α5 selectivity of the β-carboline, methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appears as an 'upper' and 'lower' moiety in the pocket. Structural data and radioligand binding data reveal a positional displacement of the upper moiety containing the isoxazole between the NAMs and PAMs. Using a hybrid molecule we directly measure the functional contribution of the upper moiety to NAM versus PAM activity. Overall, these structures provide a framework by which to understand distinct ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | text/xml; application/pdf; application/zip |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/362300Test |
| الإتاحة: | https://www.repository.cam.ac.uk/handle/1810/362300Test |
| حقوق: | Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.FC363A1B |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |