Abstract
Helicoverpa armigera is a devastating polyphagous and cosmopolitan crop pest. There are reports of this insect being resistant to a variety of pesticides raising concern worldwide. The Octopamine (OA) binding β2-like receptor (OAR), a GPCR, is widely distributed in the nervous system of the insect and plays essential roles in the physiology and development and thus is an important target for insecticides. Yet, the molecular characterization of the H. armigera OAR (HarmOAR) and rational design of compounds based on this receptor is lacking. As a first step, we performed multiple sequence alignment of all insect OARs, which revealed that the sequences contained all conserved class A GPCR motifs. Phylogenetic studies showed clade-specific variations in the protein sequences primarily arising owing to differences in the ICL3 loop region. Further, a structural model of HarmOAR was built using the inactive human β2AR as a template. 0.9 µs atomistic simulations revealed conserved inter helical contacts and water molecules of HarmOAR. The detailed binding of octopamine was studied using molecular docking and 0.3 µs atomistic simulations. Twenty-two insecticides active against octopamine receptors of other insects were compiled and docked to HarmOAR followed by rescoring with binding free energies to prioritize them for H. armigera. Our study suggests α-terpineol to be a good candidate as an insecticide or insect repellent for Helicoverpa armigera.
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Caers J, Verlinden H, Zels S, Vandersmissen HP, Vuerinckx K, Schoofs L (2012) More than two decades of research on insect neuropeptide GPCRs: an overview. Front Endocrinol 3:151
Chelikani P, Hornak V, Eilers M, Reeves PJ, Smith SO, RajBhandary UL, Khorana HG (2007) Role of group-conserved residues in the helical core of beta2-adrenergic receptor. Proc Natl Acad Sci USA 104:7027–7032. https://doi.org/10.1073/pnas.0702024104
Cherezov V et al (2007) High-resolution crystal structure of an engineered human β2-adrenergic G protein–coupled receptor. Science 318:1258–1265
Cvicek V, Goddard WA III, Abrol R (2016) Structure-based sequence alignment of the transmembrane domains of all human GPCRs: phylogenetic, structural and functional implications. PLoS Comput Biol 12:e1004805
Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego Biovia (2017) Materials Studio R2 Dassault Systèmes BIOVIA, San Diego
Enan E (2001) Insecticidal activity of essential oils: octopaminergic sites of action. Comp Biochem Physiol C Toxicol Pharmacol 130:325–337. https://doi.org/10.1016/s1532-0456(01)00255-1
Evans PD (1993) Molecular studies on insect octopamine receptors. EXS 63:286–296. https://doi.org/10.1007/978-3-0348-7265-2_16
Farooqui T (2012) Review of octopamine in insect nervous systems. Open Access Insect Physiol. https://doi.org/10.2147/oaip.S20911
Friesner RA et al (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 49:6177–6196. https://doi.org/10.1021/jm051256o
Gullan PJ, Cranston PS (2014) The insects: an outline of entomology. Wiley, New York
Hanlon CD, Andrew DJ (2015) Outside-in signaling–a brief review of GPCR signaling with a focus on the Drosophila GPCR family. J Cell Sci 128:3533–3542. https://doi.org/10.1242/jcs.175158
Harder E et al (2016) OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput 12:281–296. https://doi.org/10.1021/acs.jctc.5b00864
Hill CA, Sharan S, Watts VJ (2018) Genomics, GPCRs and new targets for the control of insect pests and vectors. Curr Opin Insect Sci 30:99–106. https://doi.org/10.1016/j.cois.2018.08.010
Huang J, MacKerell AD Jr (2013) CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data. J Comput Chem 34:2135–2145
Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(33–38):27–38. https://doi.org/10.1016/0263-7855(96)00018-5
Hunter S et al (2009) InterPro: the integrative protein signature database. Nucleic Acids Res 37:D211–D215
Lam F, McNeil JN, Donly C (2013) Octopamine receptor gene expression in three lepidopteran species of insect. Peptides 41:66–73. https://doi.org/10.1016/j.peptides.2012.03.034
Laskowski RA, Rullmannn JA, MacArthur MW, Kaptein R, Thornton JM (1996) AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR 8:477–486. https://doi.org/10.1007/BF00228148
Meng EC, Pettersen EF, Couch GS, Huang CC, Ferrin TE (2006) Tools for integrated sequence-structure analysis with UCSF Chimera. BMC Bioinf 7:339
Nathanson JA, Hunnicutt EJ, Kantham L, Scavone C (1993) Cocaine as a naturally occurring insecticide. Proc Natl Acad Sci USA 90:9645–9648
Nomiyama H, Yoshie O (2015) Functional roles of evolutionary conserved motifs and residues in vertebrate chemokine receptors. J Leukoc Biol 97:39–47. https://doi.org/10.1189/jlb.2RU0614-290R
Notredame C, Higgins DG, Heringa J (2000) T-Coffee: a novel method for fast and accurate multiple sequence alignment. J Mol Biol 302:205–217. https://doi.org/10.1006/jmbi.2000.4042
Ohta H, Ozoe Y (2014) Molecular signalling, pharmacology, and physiology of octopamine and tyramine receptors as potential insect pest control targets. In: Cohen E (ed) Advances in insect physiology, vol 46. Elsevier, Amsterdam, pp 73–166
Orr G, Gole J, Downer R (1985) Characterisation of an octopamine-sensitive adenylate cyclase in haemocyte membrane fragments of the American cockroach Periplaneta americana L. Insect Biochem 15:695–701
Pronk S et al (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29:845–854. https://doi.org/10.1093/bioinformatics/btt055
Release S (2016) 2: Maestro. Schrödinger, LLC, New York, NY
Roeder T (1990) High-affinity antagonists of the locust neuronal octopamine receptor. Eur J Pharmacol 191:221–224. https://doi.org/10.1016/0014-2999(90)94151-m
Roeder T, Degen J, Gewecke M (1998) Epinastine, a highly specific antagonist of insect neuronal octopamine receptors. Eur J Pharmacol 349:171–177. https://doi.org/10.1016/s0014-2999(98)00192-7
Tieleman D, Berendsen H (1998) A molecular dynamics study of the pores formed by Escherichia coli OmpF porin in a fully hydrated palmitoyloleoylphosphatidylcholine bilayer. Biophys J 74:2786–2801
Trifinopoulos J, Nguyen LT, von Haeseler A, Minh BQ (2016) W-IQ-TREE: a fast online phylogenetic tool for maximum likelihood analysis. Nucleic Acids Res 44:W232-235. https://doi.org/10.1093/nar/gkw256
Vanommeslaeghe K et al (2010) CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem 31:671–690
Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM (2013) Molecular signatures of G-protein-coupled receptors. Nature 494:185–194. https://doi.org/10.1038/nature11896
Venkatakrishnan AJ et al (2019) Diverse GPCRs exhibit conserved water networks for stabilization and activation. Proc Natl Acad Sci USA 116:3288–3293. https://doi.org/10.1073/pnas.1809251116
Wacker D et al (2013) Structural features for functional selectivity at serotonin receptors. Science 340:615–619
Wallace AC, Laskowski RA, Thornton JM (1995) LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng 8:127–134. https://doi.org/10.1093/protein/8.2.127
Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35:W407–W410
Wu SF, Xu G, Qi YX, Xia RY, Huang J, Ye GY (2014) Two splicing variants of a novel family of octopamine receptors with different signaling properties. J Neurochem 129(1):37–47
Acknowledgements
MJ and NG thank Bioinformatics Centre for infrastructure support. RJ would like to acknowledge the support provided by CSIR-National Chemical Laboratory as a start-up fund. SN thanks the Department of Biotechnology, India, for fellowship.
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Gujar, N., V. Nikte, S., Joshi, R.S. et al. Molecular Characterization of the β2-like Octopamine Receptor of Helicoverpa armigera. J Membrane Biol 254, 311–319 (2021). https://doi.org/10.1007/s00232-021-00172-3
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DOI: https://doi.org/10.1007/s00232-021-00172-3