Research Repository

Modeling Active GPCR Conformations

Taddese, Bruck and Simpson, Lisa M and Wall, Ian D and Blaney, Frank E and Reynolds, Christopher A (2013) 'Modeling Active GPCR Conformations.' G PROTEIN COUPLED RECEPTORS: MODELING, ACTIVATION, INTERACTIONS AND VIRTUAL SCREENING, 522. pp. 21-35. ISSN 0076-6879

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The most significant advance in modeling GPCR active states has been the β2-adrenergic receptor-Gs complex as this essentially transforms active-state modeling into homology modeling. Various different molecular dynamics-based approaches for modeling active states are presented, and a number of key applications discussed. These simulations have given insights into the activation pathway, conformational changes, dimerization, hydration, the ionic lock, ligand binding, protonation, and sodium binding. Crystallography and simulations have shown that the presence of agonist alone is unlikely to be sufficient to form the active state and that restraints applied to the G protein-binding region are required. The role of various microswitches in activation is discussed, including the controversial rotamer toggle switch. The importance of explicitly simulating experimental molecular probes to understand activation is highlighted, along with the need to ensure that such molecules are well parameterized. Approaches to loop modeling are discussed. We argue that the role of successful virtual screening against active models should not be overestimated as the main conformational changes on activation occur in the intracellular region. © 2013 Elsevier Inc.

Item Type: Article
Uncontrolled Keywords: Animals; Humans; Protons; GTP-Binding Protein alpha Subunits, Gs; Receptors, Adrenergic, beta-2; Adrenergic beta-Agonists; Protein Structure, Secondary; Protein Structure, Tertiary; Structural Homology, Protein; Algorithms; Thermodynamics; Molecular Dynamics Simulation
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 08 Jan 2015 10:50
Last Modified: 18 Aug 2022 11:15

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