Abstract

Introduction

Interactions of the Tyr-4 and Phe-8 agonist switches:

An induced-fit model for activation of the AT1 receptor:

References:

Figure Legends

Discussion
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The receptors for angiotensin II (Ang II) belong to the G-protein coupled receptor (GPCR) superfamily. To understand the mechanism of activation of function, we have studied structural analogs of Ang II in combination with site-directed mutants of the the Ang II type 1 (AT1) receptor. The AT1 receptor is prototypical: the unliganded receptor is in an inactive state (R), and the transition to active state (R*) requires the binding of Ang II to the receptor. Direct interaction of the agonist switches in Ang II with constraining residues in the receptor is responsible for not only the activation of the receptor but also the specificity of the ligand which generates an intermediate state (RÕ) that partially conforms to the R* state. Based on the assumption that the active conformation of the GPCRs is unique, it has been argued that the agonist-induced conformational change cannot affect the magnitude of response for two different agonists because such an induced-fit would alter the activation efficiency for both to an equal extent. Contrary to this belief we show that agonist-specific conformational changes persist in the activated receptor and agonist-specificity is linked to conformational differences between ligand-receptor complex for a good agonist and the corresponding complex for a poor agonist. We propose that conformational differences generated via Òinduced-fitÓ in the RÕ state determine specificity and efficacy of agonists.

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Presentation Number SAmiura0607
Keywords: Ang II, GPCRs, Active-Receptor, Agonist Switch, Induction