Investigating the role of ICL3 in β1-adrenergic receptor activation
type: CreativeWork
description: G protein-coupled receptors (GPCRs) are 7-transmembrane (7-TM) alpha helical membrane proteins involved in a myriad of physiological functions and have implications in many diseases. GPCRs are important targets for ~35% of commercial drugs. Activation of GPCRs by external signals and through coupling to different G proteins or arrestins, results in cyclic adenosine monophosphate (cAMP) response, calcium mobilization, or phosphorylation of extracellular regulated protein kinases. Structural studies have provided detailed insight into the receptor architecture in active and inactive states of the receptors. However, GPCRs are dynamic and have a complex energy landscape as they regulate complex downstream signaling processes. The thermostable turkey β1-adrenergic receptor (tβ1AR) is a prototypical class A GPCR widely used in structural studies and is activated by catecholamine ligands, adrenaline, and noradrenaline. Although many crystal structures of tβ1AR are published, there is little known about the intracellular loop 3 (ICL3) – connecting transmembrane helices 5 and 6. It is usually truncated in crystallographic studies as it interferes with the lattice formation and is replaced with T4 lysozyme to enhance crystal contacts. In some active state crystal structures (3SN6, 3POG) of GPCRs, the ICL3 is present but cannot be resolved using X-ray diffraction because of its highly dynamic nature. Thus, a more suitable technique such as nuclear magnetic resonance (NMR) spectroscopy is needed to study the dynamic nature of this low complexity region in these receptors. In this thesis, I have investigated β1AR conformational dynamics by creating a chimera of tβ1AR transmembrane domain with the flexible ICL3 from human β1AR (hICL3). The position of ICL3 is close to the G protein binding site and hypothesized to have a role in binding specificity of the receptor with intracellular binding partners. This thesis provides a comprehensive analysis for characterization of the confo…
abstract: G protein-coupled receptors (GPCRs) are 7-transmembrane (7-TM) alpha helical membrane proteins involved in a myriad of physiological functions and have implications in many diseases. GPCRs are important targets for ~35% of commercial drugs. Activation of GPCRs by external signals and through coupling to different G proteins or arrestins, results in cyclic adenosine monophosphate (cAMP) response, calcium mobilization, or phosphorylation of extracellular regulated protein kinases. Structural studies have provided detailed insight into the receptor architecture in active and inactive states of the receptors. However, GPCRs are dynamic and have a complex energy landscape as they regulate complex downstream signaling processes. The thermostable turkey β1-adrenergic receptor (tβ1AR) is a prototypical class A GPCR widely used in structural studies and is activated by catecholamine ligands, adrenaline, and noradrenaline. Although many crystal structures of tβ1AR are published, there is little known about the intracellular loop 3 (ICL3) – connecting transmembrane helices 5 and 6. It is usually truncated in crystallographic studies as it interferes with the lattice formation and is replaced with T4 lysozyme to enhance crystal contacts. In some active state crystal structures (3SN6, 3POG) of GPCRs, the ICL3 is present but cannot be resolved using X-ray diffraction because of its highly dynamic nature. Thus, a more suitable technique such as nuclear magnetic resonance (NMR) spectroscopy is needed to study the dynamic nature of this low complexity region in these receptors. In this thesis, I have investigated β1AR conformational dynamics by creating a chimera of tβ1AR transmembrane domain with the flexible ICL3 from human β1AR (hICL3). The position of ICL3 is close to the G protein binding site and hypothesized to have a role in binding specificity of the receptor with intracellular binding partners. This thesis provides a comprehensive analysis for characterization of the confo…
author: Tandale, Aditi
language: eng
keywords: GPCR, β1AR, NMR, downstream signaling
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2022-04-16
date modified: 2026-07-22T22:24:00Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.93761