Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

Deganutti, Giuseppe; Atanasio, Silvia; Rujan, Roxana Maria; Sexton, Patrick M.; Wootten, Denise; Reynolds, Christopher A.

doi:10.3389/fmolb.2021.720561

Cited by 9 publications

(9 citation statements)

References 90 publications

(126 reference statements)

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“…Solution structures of other peptide ligands that bind to secretin family GPCRs tend to be more disorganized and form an extended α -helix only upon binding. This difference in the ability of a receptor to induce secondary structure in peptide ligands upon binding may help to explain why the RAMPs only appear to act as ligand-binding selectivity switches for CALCRL-RAMP or CALCR-RAMP complexes ( Liang et al, 2020b ; Deganutti et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins

et al. 2022

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G protein-coupled receptors (GPCRs) are known to interact with several other classes of integral membrane proteins that modulate their biology and pharmacology. However, the extent of these interactions and the mechanisms of their effects are not well understood. For example, one class of GPCR-interacting proteins, receptor activity-modifying proteins (RAMPs), comprise three related and ubiquitously expressed single-transmembrane span proteins. The RAMP family was discovered more than two decades ago, and since then GPCR–RAMP interactions and their functional consequences on receptor trafficking and ligand selectivity have been documented for several secretin (class B) GPCRs, most notably the calcitonin receptor-like receptor. Recent bioinformatics and multiplexed experimental studies suggest that GPCR–RAMP interactions might be much more widespread than previously anticipated. Recently, cryo-electron microscopy has provided high-resolution structures of GPCR–RAMP–ligand complexes, and drugs have been developed that target GPCR–RAMP complexes. In this review, we provide a summary of recent advances in techniques that allow the discovery of GPCR–RAMP interactions and their functional consequences and highlight prospects for future advances. We also provide an up-to-date list of reported GPCR–RAMP interactions based on a review of the current literature. Significance Statement Receptor activity-modifying proteins (RAMPs) have emerged as modulators of many aspects of G protein-coupled receptor (GPCR)biology and pharmacology. The application of new methodologies to study membrane protein–protein interactions suggests that RAMPs interact with many more GPCRs than had been previously known. These findings, especially when combined with structural studies of membrane protein complexes, have significant implications for advancing GPCR-targeted drug discovery and the understanding of GPCR pharmacology, biology, and regulation.

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Section: Introductionmentioning

confidence: 99%

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins

et al. 2022

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“…While the ECD, where the peptide C-terminus initially recognizes class B1 GPCRs, remains less well-resolved than other regions, the resolution of structures determined through cryo-EM has drastically improved over the past five years through advances in sample preparation, data collection, and data processing, and is predicted to continue improving with sub-2.5 Å cryo-EM structure determination being increasingly routine for class B1 GPCR–G protein complexes [ 288 ]. Moreover, direct information on 3D conformational dynamics captured during vitrification can increasingly be extracted through sophisticated analytical methods [ 304 , 345 ] and such dynamics play critical roles in peptide recognition and modes of receptor activation that may not be apparent from high-resolution consensus reconstructions [ 304 , 332 , 346 , 347 ]. This information can be integrated with other methods for interrogating GPCR dynamics, including hydrogen deuterium exchange mass spectrometry (HDX-MS) [ 348 ], single-molecule FRET studies [ 349 ] and electron paramagnetic resonance (EPR) [ 350 , 351 ] and holds promise for further enhancing peptide drug design [ 348 , 352 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors

Piper

Zhao

et al. 2022

IJMS

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Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Vasoactive Intestinal Peptide (VIP) are neuropeptides involved in a diverse array of physiological and pathological processes through activating the PACAP subfamily of class B1 G protein-coupled receptors (GPCRs): VIP receptor 1 (VPAC1R), VIP receptor 2 (VPAC2R), and PACAP type I receptor (PAC1R). VIP and PACAP share nearly 70% amino acid sequence identity, while their receptors PAC1R, VPAC1R, and VPAC2R share 60% homology in the transmembrane regions of the receptor. PACAP binds with high affinity to all three receptors, while VIP binds with high affinity to VPAC1R and VPAC2R, and has a thousand-fold lower affinity for PAC1R compared to PACAP. Due to the wide distribution of VIP and PACAP receptors in the body, potential therapeutic applications of drugs targeting these receptors, as well as expected undesired side effects, are numerous. Designing selective therapeutics targeting these receptors remains challenging due to their structural similarities. This review discusses recent discoveries on the molecular mechanisms involved in the selectivity and signaling of the PACAP subfamily of receptors, and future considerations for therapeutic targeting.

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“…CGRP plays important roles in migraine pathophysiology, inflammatory response, and blood pressure ( Mehkri et al, 2022 ). At present, good progress has been made in the drug research of GCRP and CGRPR, and four related monoclonal antibodies have been developed ( Deganutti et al, 2021 ). In addition, GCRP plays an important role in the cochlea.…”

Section: Roles Of Class B1 G Protein-coupled Receptors In Cochleamentioning

confidence: 99%

“…AA2AR antagonist (istradefylline) is widely used to treat Parkinson’s disease in humans ( Merighi et al, 2022 ). However, many GPCRs extensively developed in the cochlea, such as CRFR1 ( Graham and Vetter, 2011 ), CRFR2 ( Graham et al, 2010 ), and CGRPR ( Maison et al, 2003 ) mentioned above, also have great potential in the future of cochlear therapy to treat or prevent of noise- and pharmaceutical-induced auditory toxicity ( Lowery and Thiele, 2010 ; Hauser et al, 2017 ; Deganutti et al, 2021 ). Therefore, besides existing drugs targeting GPCRs that can be further tried to be applied to the treatment of the cochlea, more structures of potential GPCRs targets are helpful to design drugs in cochlear therapy.…”

Section: Emerging G Protein-coupled Receptor-based Treatmentmentioning

confidence: 99%

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

Guo²,

Fu³

et al. 2022

Front. Mol. Neurosci.

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The prevalence of hearing loss-related diseases caused by different factors is increasing worldwide year by year. Currently, however, the patient’s hearing loss has not been effectively improved. Therefore, there is an urgent need to adopt new treatment measures and treatment techniques to help improve the therapeutic effect of hearing loss. G protein-coupled receptors (GPCRs), as crucial cell surface receptors, can widely participate in different physiological and pathological processes, particularly play an essential role in many disease occurrences and be served as promising therapeutic targets. However, no specific drugs on the market have been found to target the GPCRs of the cochlea. Interestingly, many recent studies have demonstrated that GPCRs can participate in various pathogenic process related to hearing loss in the cochlea including heredity, noise, ototoxic drugs, cochlear structure, and so on. In this review, we comprehensively summarize the functions of 53 GPCRs known in the cochlea and their relationships with hearing loss, and highlight the recent advances of new techniques used in cochlear study including cryo-EM, AI, GPCR drug screening, gene therapy vectors, and CRISPR editing technology, as well as discuss in depth the future direction of novel GPCR-based drug development and gene therapy for cochlear hearing loss. Collectively, this review is to facilitate basic and (pre-) clinical research in this area, and provide beneficial help for emerging GPCR-based cochlear therapies.

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Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

Cited by 9 publications

References 90 publications

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins

Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

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