Asst. Prof. Dr. Necla BIRGÜL

Boğaziçi University
Molecular Biology and Genetics
Kuzey Park, 313
34342 Bebek - Istanbul
+90 (212) 359 7284
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Deorphanisation of Orphan G-Protein Coupled Receptors

G-Protein Coupled Receptors (GPCRs) are localized in cell membranes and convert extracellular signals into intracellular signals, maintaining communication. By binding the ligand to the receptor, Receptors are stimulated and undergo conformational changes, GDP/GTP conversion takes place, and heterotrimeric G proteins are dissociated into Gα and Gβγ subunits to initiate different downstream signaling to regulate many physiologic processes such as growth metabolism and homeostasis. Drugs can extracellularly affect GPCRs; therefore, more than 35% of current drugs target GPCRs, such as histamine (HRH1), serotonin, dopamine, opioid and adrenergic receptors. Despite their importance, there are still about 80 GPCR orphans.

We are trying to model those orphan GPCRs using molecular dynamics simulations to investigate receptor-ligand interactions. The binding pocket will be determined and verified with site-directed mutagenesis, and different molecular libraries will be screened to detect the molecules that bind to the GPCR. To investigate the endogenous ligand, we are trying to deorphanise it via reverse physiology by using FPLC/HPLC via fractionation, and ligands will be tested by TGFα shedding assay.

Designing next-generation Pesticides targeting insect GPCRs

Allatostatin receptor type-C is a class A GPCR responsible for the inhibition of Juvenile Hormone secretion in insects. JH is essential during developmental stages such as metamorphosis; it also functions in feeding behaviour and reproduction. AstR-C represents a potential pesticide target against the pine processionary moth (Thaumetopoea pityocampa), the main factor limiting the growth and survival of the Mediterranean pine forests. We are trying to model the receptor and perform virtual screening in different libraries to discover potential AstR-C agonists. Molecular dynamics (MD) simulations and MM-GBSA calculations will be applied to the candidate molecules. Agonist molecules are then analysed through TGF- shedding assay and in vivo lethality tests on larvae to verify their effects on insects. We design next-generation pesticides using in silico, in vitro and in vivo techniques

Selected Publications

  • Shahraki, A., Isbilir, A., Dogan, B., Lohse, M.J., Durdagi, S., Birgul-Iyison N (2021)
    Structural and Functional Characterization of Allatostatin Receptor Type-C of Thaumetopoea pityocampa, a Potential Target for Next-Generation Pest Control Agents.
    Chem Inf Model doi: 10.1021/acs.jcim.0c00985.

  • Birgul Iyison, N., Shahraki, A., Kahveci, K., Duzgun, M.B., Gun, G (2021)
    PAre Insect GPCRs Ideal Next-Generation Pesticides: Opportunities and Challenges.
    FEBS J, doi: 10.1111/febs.15708.

  • Isbilir, A., Duan Sahbaz, B., Tuncgenc, G., Bünemann, M., Lohse, M.J., Birgul N. (2002)
    Pharmacological Characterization of the Stick Insect Carausius morosus Allatostatin C Receptor with Its Endogenous Agonist.
    ACS Omega, doi: 10.1021/acsomega.0c03382