Capturing Peptide–GPCR Interactions and Their Dynamics

Kaiser, Anette; Coin, Irene

doi:10.3390/molecules25204724

Cited by 27 publications

(33 citation statements)

References 335 publications

(465 reference statements)

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“…Another unresolved challenge is understanding the impact of ligand dynamics on receptor activation, in particular for peptide-activated GPCRs (reviewed in Ref. [182]). There is a growing body of evidence from NMR studies and 3DVA of cryo-EM data that peptide ligands can sample multiple conformations when bound to a receptor [183][184][185][186].…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

The role of structural dynamics in GPCR‐mediated signaling

Hilger

2021

The FEBS Journal

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G protein-coupled receptors (GPCRs) play critical roles in the regulation of human physiology in response to a wide array of different extracellular stimuli and thus represent one of the largest groups of therapeutic drug targets. Recent advances in the structural characterization of GPCRs in different conformations and in complex with G proteins and arrestins have provided important insights into the mechanism and function of GPCRs. However, in order to truly understand the molecular basis of the functional versatility of GPCRs, the structural snapshots obtained by X-ray crystallography or cryo-EM need to be complimented with information about the conformational dynamics of receptors and their signaling complexes. In the last decade, a combination of biophysical approaches and computational studies has been utilized to examine the molecular motions of GPCRs and their transducer complexes and how they are regulated by ligands of different efficacy and bias. These studies revealed that GPCRs are highly dynamic allosteric proteins that can sample multiple conformational states. Ligands with distinct signaling profiles not only impact the conformational landscape of GPCRs but also of the receptor-engaged G proteins and arrestins. The conformational dynamics of GPCRs and their signaling complexes and the ligand-dependent bias sampling of distinct functional states are important underlying principles behind the complex signaling behavior of GPCRs.

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Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

The role of structural dynamics in GPCR‐mediated signaling

Hilger

2021

The FEBS Journal

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“…Cross-linking ncAAs have been widely applied to GPCR studies (reviewed in Ref. [81]) and most recently to arr-GPCR interaction studies. Gagnon et al [82] incorporated the photo-activatable ncAA p-azido-phenylalanine (Azi) into the intracellular domains of the angiotensin II receptor type 1 (AT 1 R).…”

Section: Mapping the Arrestin-gpcr Interaction Surface Via Cross-linkingmentioning

confidence: 99%

“…Cross‐linking ncAAs have been widely applied to GPCR studies (reviewed in Ref. [81]) and most recently to arr–GPCR interaction studies. Gagnon et al .…”

Section: Identifying Functional Hot Spots Of Arrestin By Mutagenesismentioning

confidence: 99%

Biochemical insights into structure and function of arrestins

Aydin

Coin

2021

The FEBS Journal

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Arrestins (arr) are multifunctional cytosolic adaptors that bind to active and phosphorylated G protein-coupled receptors (GPCRs) via a highly versatile interface. Arrestins stop G protein signaling and trigger other signaling pathways. Recently, 3D structures of arr-GPCR complexes have been solved, which provide a bulk of structural information for understanding the mechanism of arr recruitment and activation. However, many questions about the functional consequences of structural details and the dynamics of the arr-GPCR interaction remain open. A wealth of information about key determinants for the arr-GPCR interaction and their functional relevance, and dynamic insights into the process of arr binding and the functional outcomes of different binding modes have been provided by a series of biochemical methods which we review here. Importantly, most of these methods provide information from the live cell, which is a necessary validation and complement for structural data. With the main focus on the most recent research, we will highlight major findings about arr structure, function, and dynamics derived from mutagenesis studies, cross-linking studies, conformational probes, and sensors, and we summarize available systems to detect arr recruitment. Furthermore, we discuss recent findings and directions of in silico investigations in arr-GPCR complexes.

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“…In terms of structure, GPCRs are characterized by an extracellular N-terminus, followed by seven transmembrane α-helices connected by three intracellular and three extracellular loops and finally an intracellular C-terminus. These receptors undergo conformational changes that facilitate the binding and activation of multiple effectors [ 100 ]. In this field, Caporale et al reported a hierarchical approach based on the hypothesis that a stable, amphipathic α-helix of the N-terminal fragment of the parathyroid hormone was a prerequisite for the binding and activation of its receptor (PTH1R).…”

Section: Peptides As “Tools” For (Bio)supramolecular Interactionmentioning

confidence: 99%

Peptide–Protein Interactions: From Drug Design to Supramolecular Biomaterials

2021

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The self-recognition and self-assembly of biomolecules are spontaneous processes that occur in Nature and allow the formation of ordered structures, at the nanoscale or even at the macroscale, under thermodynamic and kinetic equilibrium as a consequence of specific and local interactions. In particular, peptides and peptidomimetics play an elected role, as they may allow a rational approach to elucidate biological mechanisms to develop new drugs, biomaterials, catalysts, or semiconductors. The forces that rule self-recognition and self-assembly processes are weak interactions, such as hydrogen bonding, electrostatic attractions, and van der Waals forces, and they underlie the formation of the secondary structure (e.g., α-helix, β-sheet, polyproline II helix), which plays a key role in all biological processes. Here, we present recent and significant examples whereby design was successfully applied to attain the desired structural motifs toward function. These studies are important to understand the main interactions ruling the biological processes and the onset of many pathologies. The types of secondary structure adopted by peptides during self-assembly have a fundamental importance not only on the type of nano- or macro-structure formed but also on the properties of biomaterials, such as the types of interaction, encapsulation, non-covalent interaction, or covalent interaction, which are ultimately useful for applications in drug delivery.

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Capturing Peptide–GPCR Interactions and Their Dynamics

Cited by 27 publications

References 335 publications

The role of structural dynamics in GPCR‐mediated signaling

The role of structural dynamics in GPCR‐mediated signaling

Biochemical insights into structure and function of arrestins

Peptide–Protein Interactions: From Drug Design to Supramolecular Biomaterials

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