scholarly journals Discovering of GPCR and GnRHR as SARS-CoV-2 binding receptors, the Scientific Breakthrough that could explain the mystery of its common symptoms with unknown aetiology. In silico research.

2021 ◽  
Author(s):  
Mahmoud Ramadan Elkazzaz ◽  
Amr Ahmed ◽  
Tamer Haydara ◽  
Israa M Shamkh ◽  
Yousry Esam-Eldin Abo-Amer
Keyword(s):  
Md Simulation ◽  
Hormone Receptors ◽  
Gonadotropin Releasing Hormone ◽  
G Protein Coupled Receptors ◽  
Spike Protein ◽  
Receptor Protein ◽  
Olfactory Neurons ◽  
Hormonal Imbalance ◽  
Hormonal Balance ◽  
G Protein Coupled

Abstract A common symptoms of COVID-19 is a change or disorder in hormonal balance and olfactory function which may persist after recovery including COVID-19-related anosmia and hypogonadism. Hormonal problems including Hypogonadism and Hypothyrodism are being observed in patients with Covid-19. Rise in cases of hormonal imbalance post COVID recovery is a cause for concern. Moreover, anosmia is a well-tolerated symptom of COVID-19, but their etiology isn't understood. The studies demonstrated that the new coronavirus could affect the central nervous system through the olfactory bulb or blood circulation. Furthermore, in addition to anosmia or hyposmia induction, as well as taste disorders, the virus may cause hormonal imbalance ,headache, eye-ache, earache, dizziness and hallucination. It was showed that G-protein coupled receptors (GPCR) and Gonadotropin-releasing hormone receptors (GnRHR), a subtype of GPCR were expressed sufficiently in olfactory region and hypothalamus as well as the lung Herein by using molecular docking and stimulation analysis, we succeeded to elucidate the direct neuroinvasive route of COVID-19 into the nasal epithelium and human brain cells which may lead to anosmia and hormonal imbalance mainly through the olfactory route by direct binding to G-protein coupled receptors (GPCR). Furthermore, we strongly suspect that binding of COVID-19 to the expressed GPCR in the lung is a main cause of ion changing disruption leading to pulmonary edema and failure. Moreover, we confirmed our results by investigating Gonadotropin-releasing hormone receptors (GnRHR) as a novel binding receptor of COVID-19. In the current study, we used PatchDock server to conduct a docking study of the SARS-CoV-2 Spike protein with both of GnHR and GPCR receptor protein. The structure of the crystal structure of the proteins were retrieved from RSCP (https://www.rcsb.org/ ) with accessions numbers (PDB ID 7BR3 and 6P9X respectively. we obtained the crystal structure of spike with accession number (PDB ID: 6VYB). The proteins are downloaded in the pdb format. The spike - receptor protein was investigated to determine the conservative residues of binding of Spike protein with the GnRHR and GPCR proteins in order to discover the ability of Spike to interact with GnRHR and GPCR receptors. We performed Molecular Dynamics (MD) Simulation to investigate the positional and conformational changes of inhibitor molecule in relation to the binding site that provides insight into the binding stability. MD simulation of the complex was carried out with the GROMACS 4.5.4 package using the GROMOS96 43a1 force field .This analysis of simulations of molecular dynamics and molecular docking showed a high affinity between Spike protein and both of GPCR and GnRHR. Results indicated that the spike binds to GNHR with binding energy (-1424.7 k.cal/mol) and to GPCR with binding energy (-1451.8 k.cal/mol). The obtained results confirmed that the native model binds to GPCR with the highest docking score of -1451.8 when compared to the other GNRHR complexes, which have the lowest binding affinity, as evidenced by the docking score of -1424.9.. These results signifies better conjugation of GNRHR to the binding pocket of the spike receptor in the RDB of the spike protein. Comparing the binding free energy of GPCR to GNRHR showed that the GNRHR protein was found to bind to the vital residues in the RBD of the spike protein. But GPCRs protein were found to bind to RDB in other place in chain B of the spike. CONCLUSIONS The COVID-19 entry receptor, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its generation is limited to a minor fraction of these neurons. A change or disorder in hormonal balance and olfactory function is a common symptom of COVID-19, but its aetiology is unknown. SARS-CoV-2 was found to bind strongly and directly to both GPCR and GnRHR which expressed sufficiently in olfactory neurons. As a result, we confirm that COVID-19 could use these receptors as a direct neuroinvasive route into human brain cells, potentially leading to long-term neurological complications and hormonal imbalance via the olfactory route. Our findings may also shed a new light on the mechanism of pulmonary edema in COVID-19 patients. Therefore ,we propose that GPCR and is involved in COVID-19 pathophysiology and can be exploited as a potential therapeutic target for COVID-19.

scholarly journals Discovering of GPCRSs and GnRHRs as SARS-CoV-2 binding receptors, the Scientific Breakthrough that could explain the observed Hypogonadism, Hypothyroidism, Anosmia, Retinol deficiency, Neurological and Menstrual disturbance among SARS-COV-2 patients.

2021 ◽  
Author(s):  
Mahmoud Ramadan Elkazzaz ◽  
Amr Ahmed ◽  
Tamer Haydara ◽  
Israa M Shamkh ◽  
Yousry Esam-Eldin Abo-Amer
Keyword(s):  
Molecular Dynamics ◽  
Md Simulation ◽  
Hormone Receptors ◽  
G Protein Coupled Receptors ◽  
Spike Protein ◽  
Olfactory Neurons ◽  
Retinol Deficiency ◽  
Hormonal Imbalance ◽  
Hormonal Balance ◽  
G Protein Coupled

Abstract Background A common symptoms of COVID-19 is a change or disorder in hormonal balance and olfactory function which may persist after recovery including COVID-19-related anosmia and hypogonadism. Hormonal problems including Hypogonadism and Hypothyroidism are being observed in patients with Covid-19. Rise in cases of hormonal imbalance post COVID recovery is a cause for concern. Moreover, anosmia is a well-tolerated symptom of COVID-19, but their aetiology isn't understood. The studies demonstrated that the new coronavirus could affect the central nervous system through the olfactory bulb or blood circulation. Furthermore, in addition to anosmia or hyposmia induction, as well as taste disorders, the virus may cause hormonal imbalance ,retinol deficiency, eye-ache, earache, dizziness and hallucination. It was showed that G-protein coupled receptors (GPCRS) and Gonadotropin-releasing hormone receptors (GnRHRs, a subtype of GPCRS), were expressed sufficiently in olfactory region and hypothalamus as well as the lung Herein by using molecular docking and stimulation analysis , we succeeded to elucidate the direct neuroinvasive route of COVID-19 into the nasal epithelium and human brain cells which may lead to anosmia and hormonal imbalance mainly through the olfactory route by direct binding to G-protein coupled receptors (GPCRS). Furthermore, we strongly suspect that binding of COVID-19 to the expressed GPCRS in the lung is a main cause of ion changing disruption leading to pulmonary edema and failure . Moreover, we confirmed our results by investigating Gonadotropin-releasing hormone receptors (GnRHRs) as a novel binding receptor of COVID-19. MethodologyIn the current study, we used PatchDock server to conduct a docking study of the SARS-CoV-2 Spike protein with both of GnRHRs and GPCRSs protein. The structure of the crystal structure of the proteins were retrieved from RSCP (https://www.rcsb.org/ ) with accessions numbers (PDB ID 7BR3 and 6P9X respectively. we obtained the crystal structure of spike with accession number (PDB ID: 6VYB). The proteins are downloaded in the pdb format. The spike - receptor protein was investigated to determine the conservative residues of binding of Spike protein with the GnRHRs and GPCRS proteins in order to discover the ability of Spike to interact with GnRHR and GPCR receptors. We performed Molecular Dynamics (MD) Simulation to investigate the positional and conformational changes of the included proteins in relation to the binding site that provides insight into the binding stability. MD simulation of the complex was carried out with the GROMACS 4.5.4 package using the GROMOS96 43a1 force field .ResultsThis analysis of simulations molecular dynamics and molecular docking showed a high affinity between Spike protein and both of GnRHRs and GPCRSs . Results indicated that the spike binds to GNRHRS with binding energy (-1424.7 k.cal/mol) and to GPCRS with binding energy (-1451.8 k.cal/mol). The obtained results confirmed that the native model binds to GPCRS with the highest docking score of ( -1451.8) when compared to the other GNRHRS complexes, which have the lowest binding affinity, as evidenced by the docking score of (-1424.9). These results signifies better conjugation of GNRHRS to the binding pocket of the spike receptor in the RDB of the spike protein . Comparing the binding free energy of GPCRS to GNRHRS showed that the GNRHRS protein was found to bind to the vital residues in the RBD of the spike protein. But GPCRSs protein were found to bind to new RDB in other place in chain B of the spike. The molecular dynamics (MD) simulations study revealed significant stability of s pike protein with the GnRHRs and GPCRS separately up to 50 ns. CONCLUSIONSThe COVID-19 entry receptor, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its generation is limited to a minor fraction of these neurons. A change or disorder in hormonal balance and olfactory function is a common symptom of COVID-19 as well as retinol deficiency , but its aetiology is unknown. SARS-CoV-2 was found to bind strongly and directly to both GPCRS and GnRHRs which expressed sufficiently in olfactory neurons. As a result, we confirm that COVID-19 could use these receptors especially GNRHRS as a direct neuroinvasive route into human brain cells, potentially leading to long-term neurological complications and hormonal imbalance in addition to retinol deficiency via the olfactory route. Our findings may also shed a new light on the mechanism of pulmonary edema in COVID-19 patients. Therefore ,we propose that GPCRS and is involved in COVID-19 pathophysiology and can be exploited as a potential therapeutic target for COVID-19

scholarly journals In silico discovery of GPCRSs and GnRHRs as Novel SARS-CoV-2 binding receptors, the Scientific Breakthrough that could explain the observed High cortisol, Appetite loss, Ansomnia and Hypogonadism, as well as Hypothyroidism, Retinol deficiency and menstrual disturbances among SARS-COV-2 patients.

2021 ◽  
Author(s):  
Mahmoud Ramadan Elkazzaz ◽  
Amr Ahmed ◽  
Ghareeb Alshuwaier ◽  
Israa M Shamkh ◽  
Yousry Esam-Eldin Abo-Amer ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
G Protein ◽  
Hormone Receptors ◽  
G Protein Coupled Receptors ◽  
Spike Protein ◽  
Appetite Loss ◽  
Olfactory Neurons ◽  
Retinol Deficiency ◽  
Hormonal Imbalance ◽  
G Protein Coupled

Abstract Background COVID-19 is known to cause chemosensory dysfunction. A common symptoms of COVID-19 is a disorder in hormonal balance and olfactory function which may persist after recovery including COVID-19-related anosmia and hypogonadism. Hormonal problems such as Hypogonadism and Hypothyrodism are being observed in patients with Covid-19. Rise in cases of hormonal imbalance post COVID recovery is a cause for concern. Moreover, anosmia is a well-tolerated symptom of COVID-19, but their aetiology isn't understood. The studies demonstrated that the new coronavirus could affect the central nervous system through the olfactory bulb or blood circulation. Furthermore, in addition to anosmia or hyposmia induction, as well as taste disorders, the virus may cause Appetite loss, High cortisol, Anxiety ,Retinol deficiency, Eye-ache, earache, Dizziness, Memory, Minstrual disturbances and hallucination. G-protein coupled receptors (GPCRSs) are well known to be expressed throughout the body, and they represent the genome's largest superfamily of signaling. It was showed that G-protein coupled receptors (GPCRS) and Gonadotropin-releasing hormone receptors (GnRHRs, a subtype of GPCRS), were expressed sufficiently in olfactory region and hypothalamus as well as thyroid gland and the human lung. It was found that GPCRs are responsible for diverse biological functions such as Appetite, Cortisol level, Smelling and Tasting regulation as well as Retinol transport and act as receptors of Thyroxin. Herein by using molecular docking and stimulation analysis , we succeeded to elucidate the direct neuroinvasive route of COVID-19 into the nasal epithelium and human brain cells which may lead to anosmia and hormonal imbalance mainly through the olfactory route by direct binding to G-protein coupled receptors (GPCRS). Furthermore, we strongly suspect that binding of COVID-19 to the expressed GPCRS in the lung is a main cause of ion changing disruption leading to pulmonary edema and failure . Moreover, we confirmed our results by investigating Gonadotropin-releasing hormone receptors (GnRHRs) as a novel binding receptor of COVID-19.MethodologyIn the current study, we used PatchDock server to conduct a docking study of the SARS-CoV-2 Spike protein with both of GnRHRs and GPCRSs protein. The structure of the crystal structure of the proteins were retrieved from RSCP (https://www.rcsb.org/ ) with accessions numbers (PDB ID 7BR3 and 6P9X respectively. we obtained the crystal structure of spike with accession number (PDB ID: 6VYB). The proteins are downloaded in the pdb format. The spike - receptor protein was investigated to determine the conservative residues of binding of Spike protein with the GnRHRs and GPCRS proteins in order to discover the ability of Spike to interact with GnRHR and GPCR receptors. We performed Molecular Dynamics (MD) Simulation to investigate the positional and conformational changes of the included proteins in relation to the binding site that provides insight into the binding stability. MD simulation of the complex was carried out with the GROMACS 4.5.4 package using the GROMOS96 43a1 force field.ResultsThis analysis of simulations molecular dynamics and molecular docking showed a high affinity between Spike protein and both of GnRHRs and GPCRSs . Results indicated that the spike binds to GNRHRS with binding energy (-1424.7 k.cal/mol) and to GPCRS with binding energy (-1451.8 k.cal/mol). The obtained results confirmed that the native model binds to GPCRS with the highest docking score of ( -1451.8) when compared to the other GNRHRS complexes, which have the lowest binding affinity, as evidenced by the docking score of (-1424.9). These results signifies better conjugation of GNRHRS to the binding pocket of the spike receptor in the RDB of the spike protein . Comparing the binding free energy of GPCRS to GNRHRS showed that the GNRHRS protein was found to bind to the vital residues in the RBD of the spike protein. But GPCRSs protein were found to bind to new RDB in other place in chain B of the spike. The molecular dynamics (MD) simulations study revealed significant stability of s pike protein with the GnRHRs and GPCRS separately up to 50 ns.CONCLUSIONSThe COVID-19 entry receptor, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its generation is limited to a minor fraction of these neurons. A change or disorder in hormonal balance and olfactory function is a common symptom of COVID-19 as well as Appetite loss and retinol deficiency , but its aetiology is unknown. SARS-CoV-2 was found to bind strongly and directly to both GPCRS and GnRHRs which expressed sufficiently in olfactory neurons. As a result, we confirm that COVID-19 could use these receptors especially GNRHRS as a direct neuroinvasive route into human brain cells, potentially leading to long-term neurological complications and hormonal imbalance in addition to Appetite loss and retinol deficiency via the olfactory route. Our findings may also shed a new light on the mechanism of pulmonary edema in COVID-19 patients. Therefore ,we propose that GPCRS and is involved in COVID-19 pathophysiology and can be exploited as a potential therapeutic target for COVID-19.

scholarly journals Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects

2021 ◽  
Vol 22 (22) ◽  
pp. 12329
Author(s):  
Alfredo Ulloa-Aguirre ◽  
Teresa Zariñán ◽  
Eduardo Jardón-Valadez
Keyword(s):  
Plasma Membrane ◽  
G Protein ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Therapeutic Interventions ◽  
Endocrine Function ◽  
Receptor Protein ◽  
G Protein Coupled

Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.

A cloning strategy for G-protein-coupled hormone receptors: the ovine beta 1-adrenergic receptor

1995 ◽  
Vol 7 (3) ◽  
pp. 521 ◽  
Author(s):  
JF Padbury ◽  
YT Tseng ◽  
JA Waschek
Keyword(s):  
G Protein ◽  
Sequence Homology ◽  
Hormone Receptors ◽  
Genomic Library ◽  
Receptor Gene ◽  
G Protein Coupled Receptors ◽  
Transcriptional Level ◽  
Fetal Life ◽  
Single Clone ◽  
G Protein Coupled

Regulation of beta 1-adrenergic receptors is unusual in developing animals. For example, glucocorticoid-and thyroid hormone-responsiveness for several genes is seen in animals treated during fetal life but beta 1-responsiveness is not seen until after birth. In order to investigate this at the transcriptional level, the ovine beta 1 receptor gene was cloned from a sheep genomic library. An approach using high-stringency screening with cDNA probes and oligonucleotides from regions of human and rat genes conserved but unique to the beta 1 receptor but not to other seven transmembrane, G-protein-coupled receptors. Over 800,000 clones were screened from which 40-50 positive clones were identified by each of the probes. There was, however, only a single clone which was recognized by each of the probes. A 5-kb insert was subcloned and shown to contain sequences which hybridized to each of the probes. Using the restriction map of the rat beta 1 receptor, a 1.0-kb Pst1 internal fragment was further subcloned for sequence identification. Confirmation of this fragment as the ovine beta 1 receptor was based on homology of the beta 1 receptor from other species and tissue distribution of mRNA. Nucleotide sequence homology was 93% with the human beta 1 receptor and 84% with rat. Amino acid sequence homology was > 75% and approached 100% in the transmembrane regions. The approach described represents a practical approach to cloning and identification of hormone receptors from the highly homologous members of the seven-transmembrane, G-protein-coupled receptors.

Heteromerization As a Mechanism Modulating the Affinity of the ACE2 Receptor to the Receptor Binding Domain of SARS-CoV-2 Spike Protein

2020 ◽  
Vol 18 ◽  
Author(s):  
Diego Guidolin ◽  
Cinzia Tortorella ◽  
Deanna Anderlini ◽  
Manuela Marcoli ◽  
Guido Maura
Keyword(s):  
Receptor Binding ◽  
Binding Domain ◽  
G Protein Coupled Receptors ◽  
Spike Protein ◽  
Macromolecular Complex ◽  
Receptor Binding Domain ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2 ◽  
Quaternary Structures ◽  
G Protein Coupled

Background: Angiotensin Converting Enzyme 2 (ACE2) is primarily involved in the maturation of angiotensin. It also represents the main receptor for the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) that caused the serious epidemics COVID-19. Available evidence indicates that at the cell membrane ACE2 can form heteromeric complexes with other membrane proteins, including the amino acid transporter B0AT1 and G Protein-Coupled Receptors (GPCR). Objective: It is well known that during the formation of quaternary structures, the configuration of each single monomer is re-shaped by its interaction pattern in the macromolecular complex. Therefore, it can be hypothesized that the affinity of ACE2 to the viral receptor binding domain (RBD), when in a heteromeric complex, may depend on the associated partner. Method: By using established docking and molecular dynamics procedures, the reshaping of monomer was explored in silico to predict possible heterodimeric structures between ACE2 and GPCR, such as angiotensin and bradykinin receptors. The associated possible changes in binding affinity between the viral RBD and ACE2 when in the heteromeric complexes were also estimated. Results and Conclusion: The results provided support to the hypothesis that the heteromerization state of ACE2 may modulate its affinity to the viral RBD. If experimentally confirmed, ACE2 heteromerization may contribute to explain the observed differences in susceptibility to virus infection among individuals and to devise new therapeutic opportunities.

Corticotropin-releasing hormone receptors

2002 ◽  
Vol 30 (4) ◽  
pp. 428-432 ◽  
Author(s):  
E. W. Hillhouse ◽  
H. Randeva ◽  
G. Ladds ◽  
D. Grammatopoulos
Keyword(s):  
G Protein ◽  
Hormone Receptors ◽  
G Protein Coupled Receptors ◽  
Corticotropin Releasing Hormone ◽  
Functional Characteristics ◽  
Releasing Hormone ◽  
The Family ◽  
G Protein Coupled

Corticotropin-releasing hormone (CRH) and related peptides (urocortins, sauvagine, urotensin) play a central role in the co-ordination of autonomic, behavioural, cardiovascular, immune and endocrine responses to stressful stimuli. Their actions are mediated through activation of two types of G-protein-coupled receptors encoded by separate genes. In this review we focus on the diverse structural and functional characteristics of the family of CRH-like peptides and their receptors.

scholarly journals Parathyroid hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Alessandro Bisello ◽  
Michael Chorev ◽  
Peter A. Friedman ◽  
Tom Gardella ◽  
Rebecca Hills ◽  
...  
Keyword(s):  
Amino Acids ◽  
Parathyroid Hormone ◽  
G Protein ◽  
Hormone Receptors ◽  
G Protein Coupled Receptors ◽  
Related Peptide ◽  
Parathyroid Hormone Related Peptide ◽  
Pthrp Receptor ◽  
G Protein Coupled ◽  
Pth1 Receptor

The parathyroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [47]) are family B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor-derived peptides: PTH (84 amino acids), and PTHrP (141 amino-acids) and related peptides (PTH-(1-34), PTHrP-(1-36)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 (39 amino acids). [125I]PTH may be used to label both PTH1 and PTH2 receptors.

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