Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer

Mansoor, Samman; Kayık, Gülru; Durdağı, Serdar; Şensoy, Özge

doi:10.1016/j.csbj.2022.01.016

Cited by 8 publications

(11 citation statements)

References 61 publications

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“…In the BCM-GPR97 system, TM6 and TM7 exhibited a weak outward motion and a weak inward motion, respectively. This is a feature of active GPR97 conformation [44].…”

Section: The Palmitoylation Of G O Contributes To the High Activity O...mentioning

confidence: 91%

Mechanistic Understanding of the Palmitoylation of Go Protein in the Allosteric Regulation of Adhesion Receptor GPR97

et al. 2022

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Adhesion G-protein-coupled receptors (aGPCRs)—a major family of GPCRs—play critical roles in the regulation of tissue development and cancer progression. The orphan receptor GPR97, activated by glucocorticoid stress hormones, is a prototypical aGPCR. Although it has been established that the palmitoylation of the C-terminal Go protein is essential for Go’s efficient engagement with the active GPR97, the detailed allosteric mechanism remains to be clarified. Hence, we performed extensive large-scale molecular dynamics (MD) simulations of the GPR97−Go complex in the presence or absence of Go palmitoylation. The conformational landscapes analyzed by Markov state models revealed that the overall conformation of GPR97 is preferred to be fully active when interacting with palmitoylated Go protein. Structural and energetic analyses indicated that the palmitoylation of Go can allosterically stabilize the critical residues in the ligand-binding pocket of GPR97 and increase the affinity of the ligand for GPR97. Furthermore, the community network analysis suggests that the palmitoylation of Go not only allosterically strengthens the internal interactions between Gαo and Gβγ, but also enhances the coupling between Go and GPR97. Our study provides mechanistic insights into the regulation of aGPCRs via post-translational modifications of the Go protein, and offers guidance for future drug design of aGPCRs.

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“…In the BCM-GPR97 system, TM6 and TM7 exhibited a weak outward motion and a weak inward motion, respectively. This is a feature of active GPR97 conformation [44].…”

Section: The Palmitoylation Of G O Contributes To the High Activity O...mentioning

confidence: 91%

Mechanistic Understanding of the Palmitoylation of Go Protein in the Allosteric Regulation of Adhesion Receptor GPR97

et al. 2022

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“…[107] MD simulations have been widely used to develop traditional inhibitors [108] and non-degradative bivalent compounds. [109][110][111] Smith et al (2019) used MD simulations to asses two distinct ternary complex conformations for two VHLrecruiting PROTACs against p38δ (SJFα and SJFδ). [48] The comparative protein-protein interactions between models explained the selectivity of SJFδ for p38δ over SJFα.…”

Section: Molecular Dynamics (Md)mentioning

confidence: 99%

“…MD simulations have been widely used to develop traditional inhibitors [108] and non‐degradative bivalent compounds [109–111] . Smith et al .…”

Section: Computational Modelingmentioning

confidence: 99%

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

2023

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Degraders have illustrated that compound-induced proximity to E3 ubiquitin ligases can prompt the ubiquitination and degradation of disease-relevant proteins. Hence, this pharmacology is becoming a promising alternative and complement to available therapeutic interventions (e. g., inhibitors). Degraders rely on protein binding instead of inhibition and, hence, they hold the promise to broaden the druggable proteome. Biophysical and structural biology approaches have been the cornerstone of understanding and rationalizing degraderinduced ternary complex formation. Computational models have now started to harness the experimental data from these approaches with the aim to identify and rationally help design new degraders. This review outlines the current experimental and computational strategies used to study ternary complex formation and degradation and highlights the importance of effective crosstalk between these approaches in the advancement of the targeted protein degradation (TPD) field. As our understanding of the molecular features that govern druginduced interactions grows, faster optimizations and superior therapeutic innovations for TPD and other proximity-inducing modalities are sure to follow.

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“…Normally, class A GPCRs have seven transmembrane (TM) helices linked by three extra- and three intracellular loops (ECLs, ICLs) with the helix 8 (H8) in the intracellular C-terminus [16] , [17] . During its activation process, the endogenous AngII enters the orthosteric site located in the extracellular region of the TM bundle center.…”

Section: Introductionmentioning

confidence: 99%

Delineating the conformational landscape and intrinsic properties of the angiotensin II type 2 receptor using a computational study

Cong

Zhang

Liang

et al. 2022

Computational and Structural Biotechnology Journal

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Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer

Cited by 8 publications

References 61 publications

Mechanistic Understanding of the Palmitoylation of Go Protein in the Allosteric Regulation of Adhesion Receptor GPR97

Mechanistic Understanding of the Palmitoylation of Go Protein in the Allosteric Regulation of Adhesion Receptor GPR97

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

Delineating the conformational landscape and intrinsic properties of the angiotensin II type 2 receptor using a computational study

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