scholarly journals Insights into the Structural Basis of Endogenous Agonist Activation of Family B G Protein-Coupled Receptors

2008 ◽  
Vol 22 (6) ◽  
pp. 1489-1499 ◽  
Author(s):  
Maoqing Dong ◽  
Fan Gao ◽  
Delia I. Pinon ◽  
Laurence J. Miller
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
G Protein Coupled

scholarly journals Yeast-Based Directed-Evolution For High-Throughput Structural Stabilization of G Protein-Coupled Receptors (GPCRs)

2021 ◽  
Author(s):  
May Meltzer ◽  
Zvagelsky Tatiana ◽  
Niv Papo ◽  
Stanislav Engel
Keyword(s):  
G Protein ◽  
Resistant Cell ◽  
Single Step ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
Diffusion Method ◽  
Structural Stabilization ◽  
C Terminus ◽  
Screening Platform ◽  
G Protein Coupled

Abstract The immense potential of G protein-coupled receptors (GPCRs) as targets for drug discovery is not fully realized due to the enormous difficulties associated with structure elucidation of these profoundly unstable membrane proteins. The existing methods of GPCR stability-engineering are cumbersome and low-throughput; in addition, the scope of GPCRs that could benefit from these techniques is limited. Here, we presented a yeast-based screening platform for a single-step isolation of GRCR variants stable in the presence of short-chain detergents, a feature essential for their successful crystallization using vapor diffusion method. The detergent-resistant cell wall of yeast provides a unique compartmentalization opportunity to physically link the receptor phenotype to its encoding DNA, and thus enable discovery of stable GPCR variants with unprecedent efficiency. The scope of mutations identified by the method offers important insights into the structural basis of GPCR stability, questioning the inherent instability of the GPCR scaffold, and revealing the potential role of the C-terminus in receptor stabilization.

scholarly journals Structural Basis for Allosteric Modulation of Class B G Protein–Coupled Receptors

2020 ◽  
Vol 60 (1) ◽  
pp. 89-107 ◽  
Author(s):  
Denise Wootten ◽  
Laurence J. Miller
Keyword(s):  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
Allosteric Modulators ◽  
Class B ◽  
Endogenous Proteins ◽  
And Function ◽  
Agonist Ligands ◽  
G Protein Coupled

Recent advances in our understanding of the structure and function of class B G protein–coupled receptors (GPCRs) provide multiple opportunities for targeted development of allosteric modulators. Given the pleiotropic signaling patterns emanating from these receptors in response to a variety of natural agonist ligands, modulators have the potential to sculpt the responses to meet distinct needs of different groups of patients. In this review, we provide insights into how this family of GPCRs differs from the rest of the superfamily, how orthosteric agonists bind and activate these receptors, the potential for allosteric modulators to interact with various regions of these targets, and the allosteric influence of endogenous proteins on the pharmacology of these receptors, all of which are important considerations when developing new therapies.

scholarly journals Structural Basis for Activation of G-Protein-Coupled Receptors

2002 ◽  
Vol 91 (6) ◽  
pp. 304-312 ◽  
Author(s):  
Ulrik Gether ◽  
Fazila Asmar ◽  
Anne Kristine Meinild ◽  
Søren G. F. Rasmussen
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
G Protein Coupled

scholarly journals Structural Basis of Arrestin Selectivity for Active Phosphorylated G Protein-Coupled Receptors

2021 ◽  
Vol 22 (22) ◽  
pp. 12481
Author(s):  
Preethi C. Karnam ◽  
Sergey A. Vishnivetskiy ◽  
Vsevolod V. Gurevich
Keyword(s):  
G Protein ◽  
Receptor Binding ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
Preferential Binding ◽  
High Affinity Receptor ◽  
Functional Forms ◽  
Affinity Receptor ◽  
G Protein Coupled ◽  
Receptor Conformation

Arrestins are a small family of proteins that bind G protein-coupled receptors (GPCRs). Arrestin binds to active phosphorylated GPCRs with higher affinity than to all other functional forms of the receptor, including inactive phosphorylated and active unphosphorylated. The selectivity of arrestins suggests that they must have two sensors, which detect receptor-attached phosphates and the active receptor conformation independently. Simultaneous engagement of both sensors enables arrestin transition into a high-affinity receptor-binding state. This transition involves a global conformational rearrangement that brings additional elements of the arrestin molecule, including the middle loop, in contact with a GPCR, thereby stabilizing the complex. Here, we review structural and mutagenesis data that identify these two sensors and additional receptor-binding elements within the arrestin molecule. While most data were obtained with the arrestin-1-rhodopsin pair, the evidence suggests that all arrestins use similar mechanisms to achieve preferential binding to active phosphorylated GPCRs.

Conserved activation pathways in G-protein-coupled receptors

2012 ◽  
Vol 40 (2) ◽  
pp. 383-388 ◽  
Author(s):  
Xavier Deupi ◽  
Jörg Standfuss ◽  
Gebhard Schertler
Keyword(s):  
G Protein ◽  
Structural Changes ◽  
Transmembrane Helix ◽  
Pharmaceutical Research ◽  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Structural Basis ◽  
Structural Framework ◽  
Activation Pathways ◽  
G Protein Coupled

GPCRs (G-protein-coupled receptors) are seven-transmembrane helix proteins that transduce exogenous and endogenous signals to modulate the activity of downstream effectors inside the cell. Despite the relevance of these proteins in human physiology and pharmaceutical research, we only recently started to understand the structural basis of their activation mechanism. In the period 2008–2011, nine active-like structures of GPCRs were solved. Among them, we have determined the structure of light-activated rhodopsin with all the features of the active metarhodopsin-II, which represents so far the most native-like model of an active GPCR. This structure, together with the structures of other inactive, intermediate and active states of rhodopsin constitutes a unique structural framework on which to understand the conserved aspects of the activation mechanism of GPCRs. This mechanism can be summarized as follows: retinal isomerization triggers a series of local structural changes in the binding site that are amplified into three intramolecular activation pathways through TM (transmembrane helix) 5/TM3, TM6 and TM7/TM2. Sequence analysis strongly suggests that these pathways are conserved in other GPCRs. Differential activation of these pathways by ligands could be translated into the stabilization of different active states of the receptor with specific signalling properties.

scholarly journals The Structural Basis of Peptide Binding at Class A G Protein-Coupled Receptors

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 210
Author(s):  
Oanh Vu ◽  
Brian Joseph Bender ◽  
Lisa Pankewitz ◽  
Daniel Huster ◽  
Annette G. Beck-Sickinger ◽  
...  
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Bound State ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
Target Class ◽  
Protein Ligands ◽  
Class A ◽  
Shared Set ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) represent the largest membrane protein family and a significant target class for therapeutics. Receptors from GPCRs’ largest class, class A, influence virtually every aspect of human physiology. About 45% of the members of this family endogenously bind flexible peptides or peptides segments within larger protein ligands. While many of these peptides have been structurally characterized in their solution state, the few studies of peptides in their receptor-bound state suggest that these peptides interact with a shared set of residues and undergo significant conformational changes. For the purpose of understanding binding dynamics and the development of peptidomimetic drug compounds, further studies should investigate the peptide ligands that are complexed to their cognate receptor.

scholarly journals Non-classical amine recognition evolved in a large clade of olfactory receptors

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Qian Li ◽  
Yaw Tachie-Baffour ◽  
Zhikai Liu ◽  
Maude W Baldwin ◽  
Andrew C Kruse ◽  
...  
Keyword(s):  
Biogenic Amines ◽  
G Protein ◽  
Olfactory System ◽  
Olfactory Receptors ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
Trace Amine ◽  
G Protein Coupled ◽  
Structural Versatility ◽  
Amine Detection

Biogenic amines are important signaling molecules, and the structural basis for their recognition by G Protein-Coupled Receptors (GPCRs) is well understood. Amines are also potent odors, with some activating olfactory trace amine-associated receptors (TAARs). Here, we report that teleost TAARs evolved a new way to recognize amines in a non-classical orientation. Chemical screens de-orphaned eleven zebrafish TAARs, with agonists including serotonin, histamine, tryptamine, 2-phenylethylamine, putrescine, and agmatine. Receptors from different clades contact ligands through aspartates on transmembrane α-helices III (canonical Asp3.32) or V (non-canonical Asp5.42), and diamine receptors contain both aspartates. Non-classical monoamine recognition evolved in two steps: an ancestral TAAR acquired Asp5.42, gaining diamine sensitivity, and subsequently lost Asp3.32. Through this transformation, the fish olfactory system dramatically expanded its capacity to detect amines, ecologically significant aquatic odors. The evolution of a second, alternative solution for amine detection by olfactory receptors highlights the tremendous structural versatility intrinsic to GPCRs.

scholarly journals Endogenous agonist–bound S1PR3 structure reveals determinants of G protein–subtype bias

2021 ◽  
Vol 7 (24) ◽  
pp. eabf5325
Author(s):  
Shintaro Maeda ◽  
Yuki Shiimura ◽  
Hidetsugu Asada ◽  
Kunio Hirata ◽  
Fangjia Luo ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
Active Conformation ◽  
Vascular Integrity ◽  
Biased Signaling ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled ◽  
Alkyl Tail ◽  
Insight Into

Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the “quartet core”) exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein–coupled receptors and will help the design of biased ligands for optimized therapeutics.

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