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Article

Insights into the Interaction of LVV-Hemorphin-7 with Angiotensin II Type 1 Receptor

1
Department of Biology, College of Science, United Arab Emirates University, Al Ain PO Box 15551, UAE
2
Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia
3
Centre for Medical Research, The University of Western Australia, Crawley, WA 6009, Australia
4
Australian Research Council Centre for Personalised Therapeutics Technologies, Canberra, NSW 2609, Australia
5
School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia
6
Dimerix Limited, Nedlands, WA 6009, Australia
7
Zayed Center for Health Sciences, United Arab Emirates University, Al Ain PO Box 15551, UAE
*
Authors to whom correspondence should be addressed.
These authors contributed equally to the work.
Int. J. Mol. Sci. 2021, 22(1), 209; https://doi.org/10.3390/ijms22010209
Received: 29 October 2020 / Revised: 17 December 2020 / Accepted: 24 December 2020 / Published: 28 December 2020
(This article belongs to the Section Molecular Biology)
Hemorphins are known for their role in the control of blood pressure. Recently, we revealed the positive modulation of the angiotensin II (AngII) type 1 receptor (AT1R) by LVV-hemorphin-7 (LVV-H7) in human embryonic kidney (HEK293) cells. Here, we examined the molecular binding behavior of LVV-H7 on AT1R and its effect on AngII binding using a nanoluciferase-based bioluminescence resonance energy transfer (NanoBRET) assay in HEK293FT cells, as well as molecular docking and molecular dynamics (MD) studies. Saturation and real-time kinetics supported the positive effect of LVV-H7 on the binding of AngII. While the competitive antagonist olmesartan competed with AngII binding, LVV-H7 slightly, but significantly, decreased AngII’s kD by 2.6 fold with no effect on its Bmax. Molecular docking and MD simulations indicated that the binding of LVV-H7 in the intracellular region of AT1R allosterically potentiates AngII binding. LVV-H7 targets residues on intracellular loops 2 and 3 of AT1R, which are known binding sites of allosteric modulators in other GPCRs. Our data demonstrate the allosteric effect of LVV-H7 on AngII binding, which is consistent with the positive modulation of AT1R activity and signaling previously reported. This further supports the pharmacological targeting of AT1R by hemorphins, with implications in vascular and renal physiology. View Full-Text
Keywords: LVV-hemorphin-7; AngII; AT1R; NanoBRET; molecular docking; molecular dynamics; PAM LVV-hemorphin-7; AngII; AT1R; NanoBRET; molecular docking; molecular dynamics; PAM
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MDPI and ACS Style

Ali, A.; Johnstone, E.K.M.; Baby, B.; See, H.B.; Song, A.; Rosengren, K.J.; Pfleger, K.D.G.; Ayoub, M.A.; Vijayan, R. Insights into the Interaction of LVV-Hemorphin-7 with Angiotensin II Type 1 Receptor. Int. J. Mol. Sci. 2021, 22, 209. https://doi.org/10.3390/ijms22010209

AMA Style

Ali A, Johnstone EKM, Baby B, See HB, Song A, Rosengren KJ, Pfleger KDG, Ayoub MA, Vijayan R. Insights into the Interaction of LVV-Hemorphin-7 with Angiotensin II Type 1 Receptor. International Journal of Molecular Sciences. 2021; 22(1):209. https://doi.org/10.3390/ijms22010209

Chicago/Turabian Style

Ali, Amanat, Elizabeth K. M. Johnstone, Bincy Baby, Heng B. See, Angela Song, K. Johan Rosengren, Kevin D. G. Pfleger, Mohammed Akli Ayoub, and Ranjit Vijayan. 2021. "Insights into the Interaction of LVV-Hemorphin-7 with Angiotensin II Type 1 Receptor" International Journal of Molecular Sciences 22, no. 1: 209. https://doi.org/10.3390/ijms22010209

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