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UnknownConformational plasticity of the intracellular cavity of GPCR-G-protein complexes leads to G-protein promiscuity and selectivity.
While the dynamics of the intracellular surface in agonist-stimulated GPCRs is well studied, the impact of GPCR dynamics on G-protein selectivity remains unclear. Here, we combine molecular dynamics simulations with live-cell FRET and secondary messenger measurements, for 21 GPCR-G-protein combinati...
S-EPMC6575595 | biostudies-literature
UnknownMinute-scale persistence of a GPCR conformation state triggered by non-cognate G protein interactions primes signaling.
Despite the crowded nature of the cellular milieu, ligand-GPCR-G protein interactions are traditionally viewed as spatially and temporally isolated events. In contrast, recent reports suggest the spatial and temporal coupling of receptor-effector interactions, with the potential to diversify downstr...
S-EPMC6811539 | biostudies-literature
UnknownDynamic multimerization of Dab2-Myosin VI complexes regulates cargo processivity while minimizing cortical actin reorganization.
Myosin VI ensembles on endocytic cargo facilitate directed transport through a dense cortical actin network. Myosin VI is recruited to clathrin-coated endosomes via the cargo adaptor Dab2. Canonically, it has been assumed that the interactions between a motor and its cargo adaptor are stable. Howeve...
S-EPMC7948593 | biostudies-literature
UnknownER/K linked GPCR-G protein fusions systematically modulate second messenger response in cells.
FRET and BRET approaches are well established for detecting ligand induced GPCR-G protein interactions in cells. Currently, FRET/BRET assays rely on co-expression of GPCR and G protein, and hence depend on the stoichiometry and expression levels of the donor and acceptor probes. On the other hand, G...
S-EPMC5552854 | biostudies-literature
Unknownβ2-adrenoceptor ligand efficacy is tuned by a two-stage interaction with the Gαs C terminus.
Classical pharmacological models have incorporated an "intrinsic efficacy" parameter to capture system-independent effects of G protein-coupled receptor (GPCR) ligands. However, the nonlinear serial amplification of downstream signaling limits quantitation of ligand intrinsic efficacy. A recent biop...
S-EPMC7980469 | biostudies-literature
UnknownProtein Frustration Reveals Active Sites in Co-Evolved GPCR:G Protein Complexes and in Engineered Targeted Degrader Complexes.
The folded structure of a protein is understood to be an optimal energy state. However, previous studies have shown that certain amino acid residue positions that play a critical role in protein function are often in a suboptimal energy state or "frustrated". Here, we leverage over 1200 three-dimens...
S-EPMC12262341 | biostudies-literature
UnknownAutoregulation of GPCR signalling through the third intracellular loop.
The third intracellular loop (ICL3) of the G protein-coupled receptor (GPCR) fold is important for the signal transduction process downstream of receptor activation1-3. Despite this, the lack of a defined structure of ICL3, combined with its high sequence divergence among GPCRs, complicat...
S-EPMC10033409 | biostudies-literature
UnknownPatterning protein complexes on DNA nanostructures using a GFP nanobody.
DNA nanostructures have become an important and powerful tool for studying protein function over the last 5 years. One of the challenges, though, has been the development of universal methods for patterning protein complexes on DNA nanostructures. Herein, we present a new approach for labeling DNA n...
S-EPMC5079250 | biostudies-literature
UnknownStructural Elements in the Gαs and Gαq C Termini That Mediate Selective G Protein-coupled Receptor (GPCR) Signaling.
Although the importance of the C terminus of the α subunit of the heterotrimeric G protein in G protein-coupled receptor (GPCR)-G protein pairing is well established, the structural basis of selective interactions remains unknown. Here, we combine live cell FRET-based measurements and molecular dyna...
S-EPMC5016181 | biostudies-literature
UnknownKinase inhibitors allosterically disrupt a regulatory interaction to enhance PKCα membrane translocation.
The eukaryotic kinase domain has multiple intrinsically disordered regions whose conformation dictates kinase activity. Small molecule kinase inhibitors (SMKIs) rely on disrupting the active conformations of these disordered regions to inactivate the kinase. While SMKIs are selected for their abilit...
S-EPMC7949123 | biostudies-literature
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