How do molecular dynamics data complement static structural data of GPCRs

G protein-coupled receptors (GPCRs) are implicated in nearly every physiological process in the human body and therefore represent an important drug targeting class. Advances in X-ray crystallography and cryo-electron microscopy (cryo-EM) have provided multiple static structures of GPCRs in complex with various signaling partners. However, GPCR functionality is largely determined by their flexibility and ability to transition between distinct structural conformations. Due to this dynamic nature, a static snapshot does not fully explain the complexity of GPCR signal transduction. Molecular dynamics (MD) simulations offer the opportunity to simulate the structural motions of biological processes at atomic resolution. Thus, this technique can incorporate the missing information on protein flexibility into experimentally solved structures. Here, we review the contribution of MD simulations to complement static structural data and to improve our understanding of GPCR physiology and pharmacology, as well as the challenges that still need to be overcome to reach the full potential of this technique

In silico study of allosteric communication networks in GPCR signaling bias

Signaling bias is a promising characteristic of G protein-coupled receptors (GPCRs) as it provides the opportunity to develop more efficacious and safer drugs. This is because biased ligands can avoid the activation of pathways linked to side effects whilst still producing the desired therapeutic effect. In this respect, a deeper understanding of receptor dynamics and implicated allosteric communication networks in signaling bias can accelerate the research on novel biased drug candidates. In this review, we aim to provide an overview of computational methods and techniques for studying allosteric communication and signaling bias in GPCRs. This includes (i) the detection of allosteric communication networks and (ii) the application of network theory for extracting relevant information pipelines and highly communicated sites in GPCRs. We focus on the most recent research and highlight structural insights obtained based on the framework of allosteric communication networks and network theory for GPCR signaling bias

Ligand entry pathways control the chemical space recognized by GPR183

International audienceThe G protein-coupled receptor GPR183 utilizes two ligand entry channels: one lateral between transmembrane helices 4 and 5 facing the membrane, and one facing the extracellular environment to recognize chemically diverse ligands

Ligand entry pathways control the chemical space recognized by GPR183

The G protein-coupled receptor GPR183 is a chemotactic receptor with an important function in the immune system and association with a variety of diseases. It recognizes ligands with diverse physicochemical properties as both the endogenous oxysterol ligand 7α,25-OHC and synthetic molecules can activate the G protein pathway of the receptor. To better understand the ligand promiscuity of GPR183, we utilized both molecular dynamics simulations and cell-based validation experiments. Our work reveals that the receptor possesses two ligand entry channels: one lateral between transmembrane helices 4 and 5 facing the membrane, and one facing the extracellular environment. Using enhanced sampling, we provide a detailed structural model of 7α,25-OHC entry through the lateral membrane channel. Importantly, the first ligand recognition point at the receptor surface has been captured in diverse experimentally solved structures of different GPCRs. The proposed ligand binding pathway is supported by in vitro data employing GPR183 mutants with a sterically blocked lateral entrance, which display diminished binding and signaling. In addition, computer simulations and experimental validation confirm the existence of a polar water channel which might serve as an alternative entrance gate for less lipophilic ligands from the extracellular milieu. Our study reveals knowledge to understand GPR183 functionality and ligand recognition with implications for the development of drugs for this receptor. Beyond, our work provides insights into a general mechanism GPCRs may use to respond to chemically diverse ligands

Plasma membrane preassociation drives β-arrestin coupling to receptors and activation

beta-arrestin plays a key role in G protein-coupled receptor (GPCR) signaling and desensitization. Despite recent structural advances, the mechanisms that govern receptor-b-arrestin interactions at the plasma membrane of living cells remain elusive. Here, we combine single molecule microscopy with molecular dynamics simulations to dissect the complex sequence of events involved in b-arrestin interactions with both receptors and the lipid bilayer. Unexpectedly, our results reveal that b arrestin spontaneously inserts into the lipid bilayer and transiently interacts with receptors via lateral diffusion on the plasma membrane. Moreover,they indicate that, following receptor interaction, the plasma membrane stabilizes b-arrestin in a longer-lived, membrane-bound state, allowing it to diffuse to clathrin-coated pits separately from the activating receptor. These results expand our current understanding of b-arrestin function at the plasma membrane, revealing a critical role for b-arrestin preassociation with the lipid bilayer in facilitating its interactions with receptors and subsequent activation

Correction: Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling

Correction to: Molecular Psychiatry https://doi.org/10.1038/s41380-022-01928-6, published online 06 January 2023. In Fig. 3E of this article, the X-axis of the graph was mislabeled; Fig. 3E should have appeared as shown below.Correspondence to: [email protected] audienceNo abstract availabl

Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling

Abstract The heterogenous and dynamic constitution of the membrane fine-tunes signal transduction. In particular, the polyunsaturated fatty acid (PUFA) tails of phospholipids influence the biophysical properties of the membrane, production of second messengers, or membrane partitioning. Few evidence mostly originating from studies of rhodopsin suggest that PUFAs directly modulate the conformational dynamic of transmembrane proteins. However, whether such properties translate to other G protein-coupled receptors remains unclear. We focused on the dopamine D2 receptor (D2R), a main target of antipsychotics. Membrane enrichment in n-3, but not n-6, PUFAs potentiates ligand binding. Molecular dynamics simulations show that the D2R preferentially interacts with n-3 over n-6 PUFAs. Furthermore, even though this mildly affects signalling in heterologous systems, in vivo n-3 PUFA deficiency blunts the effects of D2R ligands. These results suggest that n-3 PUFAs act as allosteric modulators of the D2R and provide a putative mechanism for their potentiating effect on antipsychotic efficacy