Transmitting the Signal: Structure of the β1-Adrenergic Receptor-Gs Protein Complex

Pandey, Shubhi; Saha, Shirsha; Shukla, Arun K.

doi:10.1016/j.molcel.2020.09.016

Cited by 3 publications

(6 citation statements)

References 10 publications

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“…For example, the position of the α5-helix of Gα i and the finger loop of βarr1 are remarkably similar in the binding interfaces they form with the receptor (Fig. 2b), an observation that is also apparent when comparing the structures of β 1 AR-G s and β 1 AR-βarr1 complexes [11][12][13] . This typical feature appears to be responsible for how the core interaction between the receptor and βarrs precludes further G protein coupling, leading to receptor desensitization [14][15][16] .…”

mentioning

confidence: 64%

Feeling at home: Structure of the NTSR1–Gi complex in a lipid environment

Maharana

Shukla

2021

Nat Struct Mol Biol

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The interaction of G protein-coupled receptors (GPCRs) with heterotrimeric G proteins plays a critical role in signal transduction processes, and multiple GPCR-G protein complexes reconstituted in detergent micelles have been visualized using cryo-EM. A new study reports the structure of neurotensin receptor 1 (NTSR1) in complex with the heterotrimeric G i protein, assembled in a lipid environment using circularized nanodiscs. The structure sheds light on how the lipid context may influence receptor-G protein coupling and activation.GPCRS constitute a large family of cell surface proteins in the human genome, with more than 800 members, and they continue to be one of the most sought-after drug targets for a range of human disorders 1 . They exhibit incredible diversity in their ligand-recognition ability on the extracellular side but converge significantly on the transducers they are coupled with on the intracellular side. Agonist-induced activation of heterotrimeric G proteins associated with GPCRs is responsible for a broad spectrum of cellular signaling pathways involved in diverse physiological processes. The technological advance in cryo-EM has clearly revolutionized our understanding of the structural basis of GPCR activation and signaling, and the structural coverage of GPCR-G protein complexes continues to grow at a staggering pace 2 . This has resulted in cryo-EM structures of GPCRs from different subfamilies in complex with different G protein sub-types, leading to deep mechanistic understanding of coupling principles and the ensuing activation process 3 . However, the majority of the GPCR-G protein complex structures have been determined in detergent micelles, with the exception of the recent structure of the dopamine D2 receptor (DRD2) in complex with G i (ref. 4 ), which was assembled in a nanodisc-based lipid environment. Now, Zhang et al. 5 have determined the structure of the NTSR1-Gα i1 -β 1 -γ 1 complex in circularized nanodiscs (Fig. 1), which provides interesting insights into the effect of the lipid context on receptor-G protein interactions and activation.NTSR1 is a rhodopsin-like class A GPCR that is activated by a tridecapeptide neurotransmitter called neurotensin. NTSR1 signaling is involved in oncogenic growth,

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confidence: 64%

Feeling at home: Structure of the NTSR1–Gi complex in a lipid environment

Maharana

Shukla

2021

Nat Struct Mol Biol

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“…The pathway reveals that the mutation triggers frequent communication in the intracellular domains of TM3, TM5, and TM6, thus leading to a closed conformation of the intracellular end for the W318A mutant system. As indicated by the crystal studies and molecular simulations on other Class A GPCRs, the transducer binding pocket is required to be open for both G-protein and β-arrestin coupling. ,,,, The closed conformation disfavors the coupling of any downstream transducer, as evidenced by the ternary complex model above.…”

Section: Resultsmentioning

confidence: 99%

“…As indicated by the crystal studies and molecular simulations on other Class A GPCRs, the transducer binding pocket is required to be open for both G-protein and β-arrestin coupling. 67,75,96,104,105 The closed conformation disfavors the coupling of any downstream transducer, as evidenced by the ternary complex model above.…”

Section: Impact Of the W735a Mutation On Transducer Couplingmentioning

confidence: 97%

Probing Allosteric Regulation Mechanism of W7.35 on Agonist-Induced Activity for μOR by Mutation Simulation

Zhang

Chen

et al. 2021

J. Chem. Inf. Model.

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The residue located at 15 positions before the most conserved residue in TM7 (7.35 of Ballesteros–Weinstein number) plays important roles in ligand binding and the receptor activity for class A GPCRs. Nevertheless, its regulation mechanism has not been clearly clarified in experiments, and some controversies also exist for its impact on μ-opioid receptors (μOR) bound by agonists. Thus, we chose the μ-opioid receptor (μOR) of class A GPCRs as a representative and utilized a microsecond accelerated molecular dynamics simulation (aMD) coupled with a protein structure network (PSN) to explore the effect of W3187.35 on its functional activity induced by the agonist endomorphin2 mainly by a comparison of the wild system and its W7.35A mutant. When endomorphin2 binds to the wild-type μOR, TM6 in μOR moves outward to form an open intracellular conformation that is beneficial to accommodating the β-arrestin transducer, rather than the G-protein transducer due to the clash with the α5 helix of G-protein, thus acting as a β-arrestin biased agonist. However, the W318A mutation induces the intracellular part of μOR to form a closed state, which disfavors coupling with either G-protein or β-arrestin. The allosteric pathway analysis further reveals that the binding of endomorphin2 to the wild-type μOR transmits more activation signals to the β-arrestin binding site while the W318A mutation induces more structural signals to transmit to common binding residues of the G protein and β-arrestin. More interestingly, the residue at the 7.35 position regulates the shortest allosteric pathway in indirect ways by influencing the interactions between other ligand-binding residues and endomorphin2. W2936.48 and F2896.44 are important for regulating the different activities of μOR induced either by the agonist or by the mutation. Y3367.53, F3438.50, and D3408.47 play crucial roles in activating the β-arrestin biased signal induced by the agonist endomorphin2, while L1583.43 and V2866.41 devote important contributions to the change in the activity of endomorphin2 from the β-arrestin biased agonist to the antagonist upon the W318A mutation.

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“…Our structure provides a detailed view of an agonist bound in the intracellular cavity and directly interacting with a G protein. Given that G proteins require an open cavity conformation, whereas β-arrestins prefer a closed conformation 27 – 29 , the size of this cavity is considered to be pivotal for biased agonism (Fig. 3g–i and Extended Data Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Generally, the TM6 conformation is crucial for the preferential binding of specific transducers and biased signalling. Previous studies have shown that the preferential binding of G proteins requires the significant outwards movement of TM6 and a large intracellular cavity, whereas for β-arrestins, it requires a slight outwards movement of TM6 and a small intracellular cavity 27 – 29 . PCO371 acts as a molecular wedge that stabilized the significantly outwards conformation of intracellular TM6 (Fig.…”

Section: Activation Mechanism Of Pco371 Compared With Pthmentioning

confidence: 99%

Class B1 GPCR activation by an intracellular agonist

Kobayashi

Kawakami

Kusakizako

et al. 2023

Nature

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G protein-coupled receptors (GPCRs) generally accommodate specific ligands in the orthosteric-binding pockets. Ligand binding triggers a receptor allosteric conformational change that leads to the activation of intracellular transducers, G proteins and β-arrestins. Because these signals often induce adverse effects, the selective activation mechanism for each transducer must be elucidated. Thus, many orthosteric-biased agonists have been developed, and intracellular-biased agonists have recently attracted broad interest. These agonists bind within the receptor intracellular cavity and preferentially tune the specific signalling pathway over other signalling pathways, without allosteric rearrangement of the receptor from the extracellular side1–3. However, only antagonist-bound structures are currently available1,4–6, and there is no evidence to support that biased agonist binding occurs within the intracellular cavity. This limits the comprehension of intracellular-biased agonism and potential drug development. Here we report the cryogenic electron microscopy structure of a complex of Gs and the human parathyroid hormone type 1 receptor (PTH1R) bound to a PTH1R agonist, PCO371. PCO371 binds within an intracellular pocket of PTH1R and directly interacts with Gs. The PCO371-binding mode rearranges the intracellular region towards the active conformation without extracellularly induced allosteric signal propagation. PCO371 stabilizes the significantly outward-bent conformation of transmembrane helix 6, which facilitates binding to G proteins rather than β-arrestins. Furthermore, PCO371 binds within the highly conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs. Our study identifies a new and conserved intracellular agonist-binding pocket and provides evidence of a biased signalling mechanism that targets the receptor–transducer interface.

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Transmitting the Signal: Structure of the β1-Adrenergic Receptor-Gs Protein Complex

Cited by 3 publications

References 10 publications

Feeling at home: Structure of the NTSR1–Gi complex in a lipid environment

Feeling at home: Structure of the NTSR1–Gi complex in a lipid environment

Probing Allosteric Regulation Mechanism of W7.35 on Agonist-Induced Activity for μOR by Mutation Simulation

Class B1 GPCR activation by an intracellular agonist

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