scholarly journals GPCR activation mechanisms across classes and macro/microscales

2021 ◽  
Vol 28 (11) ◽  
pp. 879-888 ◽  
Author(s):  
Alexander S. Hauser ◽  
Albert J. Kooistra ◽  
Christian Munk ◽  
Franziska M. Heydenreich ◽  
Dmitry B. Veprintsev ◽  
...  
Keyword(s):  
G Proteins ◽  
Residue Level ◽  
G Protein Coupled Receptors ◽  
Conformational Selection ◽  
Class A ◽  
Allosteric Communication ◽  
Gpcr Activation ◽  
Activation Mechanisms ◽  
Clinical Drugs ◽  
G Protein Coupled

AbstractTwo-thirds of human hormones and one-third of clinical drugs activate ~350 G-protein-coupled receptors (GPCR) 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 ‘residue microswitch’ positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and methods for contact analysis applicable for any functional determinants. This provides a 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.

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.

scholarly journals Unique Features of Different Classes of G-Protein-Coupled Receptors Revealed from Sequence Coevolutionary and Structural Analysis

2021 ◽  
Author(s):  
Hung Do ◽  
Allan Haldane ◽  
Ronald Levy ◽  
Yinglong Miao
Keyword(s):  
Structural Analysis ◽  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Class A ◽  
Gpcr Activation ◽  
Residue Contacts ◽  
Critical Residue ◽  
Contact Frequency ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as the primary targets of about one third of currently marketed drugs. Despite the critical importance, experimental structures have been determined for only a limited portion of GPCRs. Functional mechanisms of GPCRs remain poorly understood. Here, we have constructed sequence coevolutionary models of the A, B and C classes of GPCRs and compared them with residue contact frequency maps generated with available experimental structures. Significant portions of structural residue contacts have been successfully detected in the sequence-based covariational models. "Exception" residue contacts predicted from sequence coevolutionary models but not available structures added missing links that were important for GPCR activation and allosteric modulation. Our combined coevolutionary and structural analysis revealed unique features of the different classes of GPCRs. First, we provided evidence from coevolutionary couplings that dimerization is required for activation of class C GPCRs, but not for activation of class A and B GPCRs. Second, we identified distinct residue contacts involving different sets of functional motifs for activation of the class A and B GPCRs. Finally, we uncovered critical residue contacts tuned by allosteric modulation in the three classes of GPCRs. These findings provide a promising framework for designing selective therapeutics of GPCRs.

scholarly journals Unique Features of Different Classes of G-Protein-Coupled Receptors Revealed from Sequence Coevolutionary and Structural Analysis

2021 ◽  
Author(s):  
Hung Do ◽  
Allan Haldane ◽  
Ronald M. Levy ◽  
Yinglong Miao
Keyword(s):  
G Protein ◽  
Rational Design ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Class A ◽  
Gpcr Activation ◽  
Residue Contacts ◽  
Critical Residue ◽  
Contact Frequency ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and represent the primary targets of about one third of currently marketed drugs. Despite the critical importance, experimental structures have been determined for only a limited portion of GPCRs and functional mechanisms of GPCRs remain poorly understood. Here, we have constructed novel sequence coevolutionary models of the A and B classes of GPCRs and compared them with residue contact frequency maps generated with available experimental structures. Significant portions of structural residue contacts were successfully detected in the sequence-based covariational models. “Exception” residue contacts predicted from sequence coevolutionary models but not available structures added missing links that were important for GPCR activation and allosteric modulation. Moreover, we identified distinct residue contacts involving different sets of functional motifs for GPCR activation, such as the Na+ pocket, CWxP, DRY, PIF and NPxxY motifs in the class A and the HETx and PxxG motifs in the class B. Finally, we systematically uncovered critical residue contacts tuned by allosteric modulation in the two classes of GPCRs, including those from the activation motifs and particularly the extracellular and intracellular loops in class A GPCRs. These findings provide a promising framework for rational design of ligands to regulate GPCR activation and allosteric modulation.

scholarly journals Structural insights into emergent signaling modes of G protein–coupled receptors

2020 ◽  
Vol 295 (33) ◽  
pp. 11626-11642 ◽  
Author(s):  
Ieva Sutkeviciute ◽  
Jean-Pierre Vilardaga
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Prescription Drugs ◽  
Helical Structure ◽  
G Protein Coupled Receptors ◽  
Gpcr Signaling ◽  
Gpcr Activation ◽  
Endosomal Membranes ◽  
G Protein Coupled ◽  
Structural Insights

G protein–coupled receptors (GPCRs) represent the largest family of cell membrane proteins, with >800 GPCRs in humans alone, and recognize highly diverse ligands, ranging from photons to large protein molecules. Very important to human medicine, GPCRs are targeted by about 35% of prescription drugs. GPCRs are characterized by a seven-transmembrane α-helical structure, transmitting extracellular signals into cells to regulate major physiological processes via heterotrimeric G proteins and β-arrestins. Initially viewed as receptors whose signaling via G proteins is delimited to the plasma membrane, it is now recognized that GPCRs signal also at various intracellular locations, and the mechanisms and (patho)physiological relevance of such signaling modes are actively investigated. The propensity of GPCRs to adopt different signaling modes is largely encoded in the structural plasticity of the receptors themselves and of their signaling complexes. Here, we review emerging modes of GPCR signaling via endosomal membranes and the physiological implications of such signaling modes. We further summarize recent structural insights into mechanisms of GPCR activation and signaling. We particularly emphasize the structural mechanisms governing the continued GPCR signaling from endosomes and the structural aspects of the GPCR resensitization mechanism and discuss the recently uncovered and important roles of lipids in these processes.

scholarly journals Interaction of class A G protein-coupled receptors with G proteins.

2004 ◽  
Vol 51 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Rafał Slusarz ◽  
Jerzy Ciarkowski
Keyword(s):  
G Protein ◽  
G Proteins ◽  
G Protein Coupled Receptors ◽  
Alpha Subunit ◽  
Protein Activation ◽  
Class A ◽  
G Protein Activation ◽  
G Protein Coupled ◽  
Receptor Dimer

A model for interaction of class A G protein-coupled receptor with the G protein G(alpha) subunit is proposed using the rhodopsin-transducin (RD/Gt) prototype. The model combines the resolved interactions/distances, essential in the active RD*/Gt system, with the structure of Gt(alpha) C-terminal peptide bound to RD* while stabilizing it. Assuming the interactions involve conserved parts of the partners, the model specifies the conserved Helix 2 non-polar X- - -X, Helix 3 DRY and Helix 7/8 NP- -Y- - F RD* motifs interacting with the Gt(alpha) C-terminal peptide, in compliance with the structure of the latter. A concomitant role of Gt(alpha) and Gt(gamma) C-termini in stabilizing RD* could possibly be resolved assuming a receptor dimer as requisite for G protein activation.

scholarly journals Multi-state Modeling of G-protein Coupled Receptors at Experimental Accuracy

2021 ◽  
Author(s):  
Lim Heo ◽  
Michael Feig
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Structural Changes ◽  
High Accuracy ◽  
G Protein Coupled Receptors ◽  
Ligand Docking ◽  
Gpcr Activation ◽  
The Family ◽  
Activation Mechanisms ◽  
G Protein Coupled

The family of G-protein coupled receptors (GPCRs) is one of the largest protein families in the human genome. GPCRs transduct chemical signals from extracellular to intracellular regions via a conformational switch between active and inactive states upon ligand binding. While experimental structures of GPCRs remain limited, high-accuracy computational predictions are now possible with AlphaFold2. However, AlphaFold2 only predicts one state and is biased towards the inactive conformation. Here, a multi-state prediction protocol is introduced that extends AlphaFold2 to predict either active or inactive states at very high accuracy using state-annotated templated GPCR databases. The predicted models accurately capture the main structural changes upon activation of the GPCR at the atomic level. The models were also highly successful in predicting ligand binding poses via protein-ligand docking. We expect that high accuracy GPCR models in both activation states will promote understanding in GPCR activation mechanisms and drug discovery for GPCRs. At the time, the new protocol paves the way towards capturing the dynamics of proteins at high-accuracy via machine-learning methods.

Gα 16/z Chimeras Efficiently Link a Wide Range of G Protein— Coupled Receptors to Calcium Mobilization

2003 ◽  
Vol 8 (1) ◽  
pp. 39-49 ◽  
Author(s):  
Andrew M.F. Liu ◽  
Maurice K.C. Ho ◽  
Cecilia S.S. Wong ◽  
Jasmine H.P. Chan ◽  
Anson H.M. Pau ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
G Protein Coupled Receptors ◽  
Imaging Plate ◽  
Response Curves ◽  
Gpcr Activation ◽  
Wide Range ◽  
Intracellular Ca ◽  
Screening Assays ◽  
G Protein Coupled

G protein—coupled receptors (GPCRs) represent a class of important therapeutic targets for drug discovery. The integration of GPCRs into contemporary high-throughput functional assays is critically dependent on the presence of appropriate G proteins. Given that different GPCRs can discriminate against distinct G proteins, a universal G protein adapter is extremely desirable. In this report, the authors evaluated two highly promiscuous Gα16/z chimeras, 16z25 and 16z44, for their ability to translate GPCR activation into Ca2+ mobilization using the fluorescence imaging plate reader (FLIPR) and aequorin. A panel of 24 Gs- or Gi-coupled receptors was examined for their functional association with the Gα16/z chimeras. Although most of the GPCRs tested were incapable of inducing Ca2+ mobilization upon their activation by specific agonists, the introduction of 16z25 or 16z44 allowed all of these GPCRs to mediate agonist-induced Ca 2+ mobilization. In contrast, only 16 of the GPCRs tested were capable of using Gα16 to mobilize intracellular Ca2+. Analysis of dose-response curves obtained with the δ-opioid, dopamine D1 , and Xenopus melatonin Mel1c receptors revealed that the Gα 16/z chimeras possess better sensitivity than Gα16 in both the FLIPR and aequorin assays. Collectively, these studies help to validate the promiscuity of the Gα16/z chimeras as well as their application in contemporary drug-screening assays that are based on ligand-induced Ca 2+ mobilization. ( Journal of Biomolecular Screening 2003:39-49)

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