scholarly journals Motions around conserved helical weak spots facilitate GPCR activation

2021 ◽  
Author(s):  
J. M. Bibbe ◽  
G. Vriend
Keyword(s):  
Gpcr Activation

scholarly journals Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

2021 ◽  
Vol 22 (6) ◽  
pp. 3241
Author(s):  
Raudah Lazim ◽  
Donghyuk Suh ◽  
Jai Woo Lee ◽  
Thi Ngoc Lan Vu ◽  
Sanghee Yoon ◽  
...  
Keyword(s):  
G Protein ◽  
Protein Interactions ◽  
Metabotropic Glutamate Receptor ◽  
Three Dimensional ◽  
Allosteric Modulation ◽  
Experimental Investigations ◽  
G Protein Coupled Receptor ◽  
Metabotropic Glutamate ◽  
Gpcr Activation ◽  
G Protein Coupled

G protein-coupled receptor (GPCR) oligomerization, while contentious, continues to attract the attention of researchers. Numerous experimental investigations have validated the presence of GPCR dimers, and the relevance of dimerization in the effectuation of physiological functions intensifies the attractiveness of this concept as a potential therapeutic target. GPCRs, as a single entity, have been the main source of scrutiny for drug design objectives for multiple diseases such as cancer, inflammation, cardiac, and respiratory diseases. The existence of dimers broadens the research scope of GPCR functions, revealing new signaling pathways that can be targeted for disease pathogenesis that have not previously been reported when GPCRs were only viewed in their monomeric form. This review will highlight several aspects of GPCR dimerization, which include a summary of the structural elucidation of the allosteric modulation of class C GPCR activation offered through recent solutions to the three-dimensional, full-length structures of metabotropic glutamate receptor and γ-aminobutyric acid B receptor as well as the role of dimerization in the modification of GPCR function and allostery. With the growing influence of computational methods in the study of GPCRs, we will also be reviewing recent computational tools that have been utilized to map protein–protein interactions (PPI).

scholarly journals Applications of molecular replacement to G protein-coupled receptors

2013 ◽  
Vol 69 (11) ◽  
pp. 2287-2292 ◽  
Author(s):  
Andrew C. Kruse ◽  
Aashish Manglik ◽  
Brian K. Kobilka ◽  
William I. Weis
Keyword(s):  
G Protein ◽  
Structural Biology ◽  
Structural Information ◽  
G Protein Coupled Receptors ◽  
Integral Membrane Proteins ◽  
Molecular Replacement ◽  
Gpcr Activation ◽  
Health And Disease ◽  
Almost All ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are a large class of integral membrane proteins involved in regulating virtually every aspect of human physiology. Despite their profound importance in human health and disease, structural information regarding GPCRs has been extremely limited until recently. With the advent of a variety of new biochemical and crystallographic techniques, the structural biology of GPCRs has advanced rapidly, offering key molecular insights into GPCR activation and signal transduction. To date, almost all GPCR structures have been solved using molecular-replacement techniques. Here, the unique aspects of molecular replacement as applied to individual GPCRs and to signaling complexes of these important proteins are discussed.

scholarly journals Thermodynamics of GPCR activation

2015 ◽  
Vol 1 (3) ◽  
pp. 115-119 ◽  
Author(s):  
Xuejun C. Zhang ◽  
Ye Zhou ◽  
Can Cao
Keyword(s):  
Gpcr Activation

GPCR activation mechanisms across classes and macro/microscales

2021 ◽  
Author(s):  
David Gloriam ◽  
Alexander Hauser ◽  
Albert Kooistra ◽  
Christian Munk ◽  
M. Madan Babu
Keyword(s):  
Residue Level ◽  
G Protein Coupled Receptors ◽  
Conformational Selection ◽  
Class A ◽  
New Methods ◽  
Allosteric Communication ◽  
Gpcr Activation ◽  
Activation Mechanisms ◽  
Clinical Drugs ◽  
G Protein Coupled

Abstract Two-thirds of human hormones and one-third of clinical drugs activate ~350 G protein-coupled receptors belonging to four classes: A, B1, C and F. Whereas a model of activation has been described for class A, very little is known about the activation of the other classes which differ by being activated by endogenous ligands bound mainly or entirely extracellularly. Here, we show that although they use the same structural scaffold and share several helix macroswitches, the GPCR classes differ in their microswitch residue positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and new methods for contact analysis applicable for any functional determinants. This is the first superfamily residue-level rationale for conformational selection and allosteric communication by ligands and G proteins laying the foundation for receptor-function studies and drugs with the desired modality.

FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs

2018 ◽  
Vol 11 (559) ◽  
pp. eaar5536 ◽  
Author(s):  
Shane C. Wright ◽  
Maria Consuelo Alonso Cañizal ◽  
Tobias Benkel ◽  
Katharina Simon ◽  
Christian Le Gouill ◽  
...  
Keyword(s):  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Group Of Seven ◽  
Stem Cell Regulation ◽  
Wnt Proteins ◽  
Gpcr Activation ◽  
Class B ◽  
Activation Profile ◽  
Functional Inactivation ◽  
Class F

Frizzleds (FZDs) are a group of seven transmembrane–spanning (7TM) receptors that belong to class F of the G protein–coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD5) is one of the most studied class F GPCRs that promote the functional inactivation of the β-catenin destruction complex in response to WNTs. However, whether FZDs function as prototypical GPCRs has been heavily debated and, in particular, FZD5 has not been shown to activate heterotrimeric G proteins. Here, we show that FZD5 exhibited a conformational change after the addition of WNT-5A, which is reminiscent of class A and class B GPCR activation. In addition, we performed several live-cell imaging and spectrometric-based approaches, such as dual-color fluorescence recovery after photobleaching (dcFRAP) and resonance energy transfer (RET)–based assays that demonstrated that FZD5 activated Gαq and its downstream effectors upon stimulation with WNT-5A. Together, these findings suggest that FZD5 is a 7TM receptor with a bona fide GPCR activation profile and suggest novel targets for drug discovery in WNT-FZD signaling.

scholarly journals An Efficient Strategy to Estimate Thermodynamics and Kinetics of G Protein-Coupled Receptor Activation Using Metadynamics and Maximum Caliber

2018 ◽  
Author(s):  
Derya Meral ◽  
Davide Provasi ◽  
Marta Filizola
Keyword(s):  
G Protein ◽  
Adaptive Sampling ◽  
Receptor Activation ◽  
Conformational Space ◽  
Kinetic Properties ◽  
G Protein Coupled Receptor ◽  
Efficient Strategy ◽  
Gpcr Activation ◽  
Kinetic Rates ◽  
G Protein Coupled

ABSTRACTComputational strategies aimed at unveiling the thermodynamic and kinetic properties of G Protein-Coupled Receptor (GPCR) activation require extensive molecular dynamics simulations of the receptor embedded in an explicit lipid-water environment. A possible method for efficiently sampling the conformational space of such a complex system is metadynamics (MetaD) with path collective variables (CV). Here, we applied well-tempered MetaD with path CVs to one of the few GPCRs for which both inactive and fully active experimental structures are available, the μ-opioid receptor (MOR), and assessed the ability of this enhanced sampling method to estimate thermodynamic properties of receptor activation in line with those obtained by more computationally expensive adaptive sampling protocols. While n-body information theory (nBIT) analysis of these simulations confirmed that MetaD can efficiently characterize ligand-induced allosteric communication across the receptor, standard MetaD cannot be used directly to derive kinetic rates because transitions are accelerated by a bias potential. Applying the principle of Maximum Caliber (MaxCal) to the free-energy landscape of morphine-bound MOR reconstructed from MetaD, we obtained Markov State Models (MSMs) that yield kinetic rates of MOR activation in agreement with those obtained by adaptive sampling. Taken together, these results suggest that the MetaD-MaxCal combination creates an efficient strategy for estimating thermodynamic and kinetic properties of GPCR activation at an affordable computational cost.

scholarly journals Modulation of A2aR Oligomerisation by Conformational State and PIP2 Interactions Revealed by MD Simulations and Markov Models

2020 ◽  
Author(s):  
Wanling Song ◽  
Anna L. Duncan ◽  
Mark S.P. Sansom
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Markov Models ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Membrane Lipid ◽  
Intracellular Loop ◽  
Gpcr Activation ◽  
State Models

AbstractG protein-coupled receptors (GPCRs) play key roles in cellular signalling. GPCRs are suggested to form dimers and higher order oligomers in response to activation. However, we do not fully understand GPCR activation at larger scales and in an in vivo context. We have characterised oligomeric configurations of the adenosine 2a receptor (A2aR) by combining large-scale molecular dynamics simulations with Markov state models. Receptor activation results in enhanced oligomerisation, more diverse oligomer populations, and a more connected oligomerisation network. The active state conformation of the A2aR shifts protein-protein association interfaces to those involving intracellular loop ICL3 and transmembrane helix TM6. Binding of PIP2 to A2aR stabilises protein-protein interactions via PIP2-mediated association interfaces. These results indicate that A2aR oligomerisation is responsive to the local membrane lipid environment. This in turn suggests a modulatory effect on A2aR whereby a given oligomerisation profile favours the dynamic formation of specific supra-molecular signalling complexes.

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