دورية أكاديمية
Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation.
| العنوان: | Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation. |
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| المؤلفون: | Rubenstein LA; Department of Physiology and Biophysics, Mount Sinai School of Medicine, One Gustav Levy Place, New York, NY 10029, USA., Zauhar RJ, Lanzara RG |
| المصدر: | Journal of molecular graphics & modelling [J Mol Graph Model] 2006 Dec; Vol. 25 (4), pp. 396-409. Date of Electronic Publication: 2006 Mar 30. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science, Inc Country of Publication: United States NLM ID: 9716237 Publication Model: Print-Electronic Cited Medium: Print ISSN: 1093-3263 (Print) Linking ISSN: 10933263 NLM ISO Abbreviation: J Mol Graph Model Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Elsevier Science, Inc., c1997- |
| مواضيع طبية MeSH: | Receptors, Adrenergic, beta-2/*chemistry , Receptors, G-Protein-Coupled/*chemistry, Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Biophysical Phenomena ; Biophysics ; Cysteine/chemistry ; In Vitro Techniques ; Mice ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Protein Conformation ; Receptors, Adrenergic, beta-2/genetics ; Receptors, G-Protein-Coupled/genetics ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Static Electricity ; Thermodynamics |
| مستخلص: | This study analyzes 16 molecular dynamic simulations of a biophysical model for beta(2)-adrenergic (B2AR) and G protein-coupled receptor (GPCR) activation. In this model, a highly conserved cysteine residue, C106 (C3.25 or CysIII:01), provides a free sulfhydryl or thiol group in an acid-base equilibrium between uncharged (RSH) and charged (RS(-)) states that functions as an electrostatic molecular switch for receptor activation. The transition of C106 in the B2AR between acid and base states significantly changes the helical/transmembrane (TM) domain interactions and the electrostatic interaction energy differences (DeltaDeltaE(EL)). The DeltaDeltaE(EL) changes correlate well with the experimentally observed ligand efficacies. The TM interaction energies display patterns compatible with those previously recognized as responsible for GPCR activation. Key differences between the agonist, epinephrine, and the antagonist, pindolol, are seen for the TM3 x 6, TM3 x 4, TM6 x 7 and TM1 x 7 interaction energies. Pindolol also produces a weaker DeltaDeltaE(EL) interaction and less TM interaction energy changes, which are important differences between the agonist and antagonist ligands. The D115E mutant with pindolol displays a greater DeltaDeltaE(EL) and TM interactions than for the wild-type B2AR with pindolol. This explains the higher activity of pindolol in the D115E mutant. The constitutively active D130A mutant displays TM interaction patterns similar to those for the activating ligands implying a common pattern for receptor activation. These findings support the broad concept of protean agonism and demonstrate the potential for allosteric modulation. They also demonstrate that this two-state model agrees with many previous experimental and theoretical observations of GPCRs. |
| المشرفين على المادة: | 0 (Receptors, Adrenergic, beta-2) 0 (Receptors, G-Protein-Coupled) 0 (Recombinant Proteins) K848JZ4886 (Cysteine) |
| تواريخ الأحداث: | Date Created: 20060401 Date Completed: 20070125 Latest Revision: 20141120 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1016/j.jmgm.2006.02.008 |
| PMID: | 16574446 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1093-3263 |
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| DOI: | 10.1016/j.jmgm.2006.02.008 |