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Structural Determinants for the Binding of Morphinan Agonists to the μ-Opioid Receptor.

التفاصيل البيبلوغرافية
العنوان: Structural Determinants for the Binding of Morphinan Agonists to the μ-Opioid Receptor.
المؤلفون: Xiaojing Cong, Pablo Campomanes, Achim Kless, Inga Schapitz, Markus Wagener, Thomas Koch, Paolo Carloni
المصدر: PLoS ONE, Vol 10, Iss 8, p e0135998 (2015)
بيانات النشر: Public Library of Science (PLoS), 2015.
سنة النشر: 2015
المجموعة: LCC:Medicine
LCC:Science
مصطلحات موضوعية: Medicine, Science
الوصف: Atomistic descriptions of the μ-opioid receptor (μOR) noncovalently binding with two of its prototypical morphinan agonists, morphine (MOP) and hydromorphone (HMP), are investigated using molecular dynamics (MD) simulations. Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations. Alchemical free energy perturbation calculations show qualitative agreement with in vitro experiments performed in this work: indeed, the binding free energy difference between MOP and HMP computed by forward and backward alchemical transformation is 1.2±1.1 and 0.8±0.8 kcal/mol, respectively, to be compared with 0.4±0.3 kcal/mol from experiment. Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor's activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond. This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1932-6203
Relation: http://europepmc.org/articles/PMC4539194?pdf=render; https://doaj.org/toc/1932-6203
DOI: 10.1371/journal.pone.0135998
URL الوصول: https://doaj.org/article/07ce42f2f7d74c9eab829753267f6531
رقم الأكسشن: edsdoj.07ce42f2f7d74c9eab829753267f6531
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:19326203
DOI:10.1371/journal.pone.0135998