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Article

Insights into the Activation of a Crustacean G Protein-Coupled Receptor: Evaluation of the Red Pigment-Concentrating Hormone Receptor of the Water Flea Daphnia pulex (Dappu-RPCH R)

1
Department of Chemistry, University of Cape Town, Private Bag, Rondebosch, Cape Town 7701, South Africa
2
Department of Biological Sciences, University of Cape Town, Private Bag, Rondebosch, Cape Town 7701, South Africa
*
Author to whom correspondence should be addressed.
Academic Editor: Dov Borovsky
Biomolecules 2021, 11(5), 710; https://doi.org/10.3390/biom11050710
Received: 12 March 2021 / Revised: 4 May 2021 / Accepted: 7 May 2021 / Published: 10 May 2021
(This article belongs to the Special Issue Insect Receptors: Biochemical, Physiological and Molecular Studies)
The validation of a previously developed model of the interaction between the red pigment-concentrating hormone of Daphnia pulex and its cognate receptor (Jackson et al., IJBM 106, 969–978, 2018) was undertaken. Single amino acid replacements, noticeably an Ala scan, of the ligand, Dappu-RPCH, were docked to the receptor, and the binding energies calculated and compared to the one with Dappu-RPCH. As a second step, the same molecules were docked using molecular dynamics (MD) in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane. Changes in binding energy were compared to previous results on in vitro receptor activation (Marco et al., Sci. Rep. 7, 6851, 2017). Residue scanning and MD simulations both gave comparable results for binding energy. For most mutants, there was a good inverse correlation between in vitro activity and binding. There were, however, exceptions; for example: [Ala4]Dappu-RPCH bound as tightly as the cognate ligand but had little activity. This seeming discrepancy was explained when the MD data were analyzed in detail, showing that, although [Ala4]Dappu-RPCH had multiple interactions with the receptor accounting for the high binding energy, the interacting residues of the receptor were quite different to those of Dappu-RPCH. The MD calculations show clearly that the strong binding affinity of the ligand to the receptor is not sufficient for activation. Interaction of the binding of the ligand to two residues of the receptor, Ser 155 and Gln 237, is also essential. A comparison of our computational results with the experimental results of Marco et al. and comparison with the extensive data on GnRH supports the validity of our Dappu-RPCH R model. View Full-Text
Keywords: crustacean red pigment-concentrating hormone receptor; Ala replacement scan; molecular docking of mutated ligands; G protein-coupled receptor crustacean red pigment-concentrating hormone receptor; Ala replacement scan; molecular docking of mutated ligands; G protein-coupled receptor
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MDPI and ACS Style

Jackson, G.E.; Gäde, G. Insights into the Activation of a Crustacean G Protein-Coupled Receptor: Evaluation of the Red Pigment-Concentrating Hormone Receptor of the Water Flea Daphnia pulex (Dappu-RPCH R). Biomolecules 2021, 11, 710. https://doi.org/10.3390/biom11050710

AMA Style

Jackson GE, Gäde G. Insights into the Activation of a Crustacean G Protein-Coupled Receptor: Evaluation of the Red Pigment-Concentrating Hormone Receptor of the Water Flea Daphnia pulex (Dappu-RPCH R). Biomolecules. 2021; 11(5):710. https://doi.org/10.3390/biom11050710

Chicago/Turabian Style

Jackson, Graham E., and Gerd Gäde. 2021. "Insights into the Activation of a Crustacean G Protein-Coupled Receptor: Evaluation of the Red Pigment-Concentrating Hormone Receptor of the Water Flea Daphnia pulex (Dappu-RPCH R)" Biomolecules 11, no. 5: 710. https://doi.org/10.3390/biom11050710

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