Analysis of ligand bias in functional studies involving the allosteric modulation of G protein‐coupled receptors (654.6)

Ligand bias is the ability of ligands to differentially activate certain receptor signaling responses compared with others. It reflects differences in the responses of a receptor to specific ligands and has implications for the development of highly specific therapeutics. Whereas ligand bias has been studied primarily for G protein–coupled receptors (GPCRs), there are also reports of ligand bias for receptor tyrosine kinases (RTKs). However, the understanding of RTK ligand bias is lagging behind the knowledge of GPCR ligand bias. In this review, we highlight how protocols that were developed to study GPCR signaling can be used to identify and quantify RTK ligand bias. We also introduce an operational model that can provide insights into the biophysical basis of RTK activation and ligand bias. Finally, we discuss possible mechanisms underpinning RTK ligand bias. Thus, this review serves as a primer for researchers interested in investigating ligand bias in RTK signaling.

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Allosteric Modulation and Thermodynamic Constraints in Occupancy Models of Oligomeric G Protein-Coupled Receptors

Biophysical Journal ◽

10.1016/j.bpj.2017.11.617 ◽

2018 ◽

Vol 114 (3) ◽

pp. 106a

Author(s):

Gregory D. Conradi Smith ◽

Richard Hammack

Keyword(s):

G Protein ◽

Allosteric Modulation ◽

G Protein Coupled Receptors ◽

Occupancy Models ◽

G Protein Coupled

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ChemInform Abstract: Allosteric Modulation of G Protein-Coupled Receptors

ChemInform ◽

10.1002/chin.200128295 ◽

2010 ◽

Vol 32 (28) ◽

pp. no-no

Author(s):

Ad Ijzerman ◽

Angeliki Kourounakis ◽

Pieter van der Klein

Keyword(s):

G Protein ◽

Allosteric Modulation ◽

G Protein Coupled Receptors ◽

G Protein Coupled

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Allosteric modulation of G protein-coupled receptors: perspectives and recent developments

Drug Discovery Today ◽

10.1016/s1359-6446(04)03220-9 ◽

2004 ◽

Vol 9 (17) ◽

pp. 752-758 ◽

Cited By ~ 60

Author(s):

Willem Soudijn ◽

Ineke van Wijngaarden ◽

Ad P. IJzerman

Keyword(s):

G Protein ◽

Allosteric Modulation ◽

G Protein Coupled Receptors ◽

Recent Developments ◽

G Protein Coupled

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

10.1101/2021.06.03.446974 ◽

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.

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

10.22541/au.162766239.98409455/v1 ◽

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.

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G protein subtype–specific signaling bias in a series of CCR5 chemokine analogs

Science Signaling ◽

10.1126/scisignal.aao6152 ◽

2018 ◽

Vol 11 (552) ◽

pp. eaao6152 ◽

Cited By ~ 12

Author(s):

Emily Lorenzen ◽

Emilie Ceraudo ◽

Yamina A. Berchiche ◽

Carlos A. Rico ◽

Alexandre Fürstenberg ◽

...

Keyword(s):

G Protein ◽

Chemokine Receptor ◽

General Feature ◽

G Protein Coupled Receptors ◽

Second Messenger Pathways ◽

Chemokine Receptor 4 ◽

Ligand Bias ◽

G Protein Coupled ◽

Hiv 1 ◽

The Ideal

Chemokines and some chemical analogs of chemokines prevent cellular HIV-1 entry when bound to the HIV-1 coreceptors C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4), which are G protein–coupled receptors (GPCRs). The ideal HIV-1 entry blocker targeting the coreceptors would display ligand bias and avoid activating G protein–mediated pathways that lead to inflammation. We compared CCR5-dependent activation of second messenger pathways in a single cell line. We studied two endogenous chemokines [RANTES (also known as CCL5) and MIP-1α (also known as CCL3)] and four chemokine analogs of RANTES (5P12-, 5P14-, 6P4-, and PSC-RANTES). We found that CCR5 signaled through both Gi/o and Gq/11. IP1 accumulation and Ca2+ flux arose from Gq/11 activation, rather than from Gβγ subunit release after Gi/o activation as had been previously proposed. The 6P4- and PSC-RANTES analogs were superagonists for Gq/11 activation, whereas the 5P12- and 5P14-RANTES analogs displayed a signaling bias for Gi/o. These results demonstrate that RANTES analogs elicit G protein subtype–specific signaling bias and can cause CCR5 to couple preferentially to Gq/11 rather than to Gi/o signaling pathways. We propose that G protein subtype–specific signaling bias may be a general feature of GPCRs that can couple to more than one G protein family.

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

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-010919-023301 ◽

2020 ◽

Vol 60 (1) ◽

pp. 89-107 ◽

Cited By ~ 7

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.

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