Thesis
Unveiling the activation mechanism of the GnRH Receptor
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2024
- Thesis identifier
- T17138
- Person Identifier (Local)
- 202176035
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- G-protein coupled receptors (GPCRs) are indispensable signallingmolecules that orchestrate a myriad of physiological processes, renderingthem pivotal therapeutic targets. Remarkably, approximately 35% ofapproved drugs modulate GPCR activity, underscoring their profoundsignificance. Nonetheless, understanding the mechanisms underpinningGPCR activation remains a challenge, particularly in the context of the GnRH1 receptor (GnRH1R). This receptor is dedicated to mediating the effects of gonadotropin-releasing hormone (GnRH) and the production of fertility hormones, exhibits unusual structural characteristics, such as the absence of a C-terminal helix and variations in what are otherwise highly conserved motifs amongst the GPCR superfamily. Unveiling the GnRH binding that triggers GnRH1R activation is imperative, and characterisation of the GnRH1R active conformation will address a critical knowledge gap.The research methodology employed a combination of computationaldocking and molecular dynamic (MD) simulations. Docking simulations wereperformed using the Rosetta software and tailored protocols for membraneproteins and flexible peptide ligands. The docking process resulted intothousands of potential GnRH binding modes which were clustered andfiltered based on criteria such as energy metrics and contacts withexperimentally important receptor residues. The binding mode eliminationprocess yielded two promising binding modes representing the native-likeGnRH-GnRH1R complex. MD simulations of the selected best rankingbinding modes were performed to investigate their ability to activate theGnRH1R. Receptor activation was monitored and evaluated by the increase of the distance between two key transmembrane helices (TM3 and TM6) - a widely accepted characteristic of GPCR activation. One of the predicted binding modes induced activation after 1.0 ?s of simulation and displayed anincreased TM3-TM6 distance (~13 Å) compared to the inactive GnRH1R (~8Å). GnRH binding displayed high stability and involved several ?? interactions, especially through tryptophan 3 (W3) and tyrosine 5 (Y5) ofGnRH and the CWxPY motif of the receptor. The crucial residue R8 of GnRHwas found to form cation-? interactions with W2806.48 of the CWxPY motif and in addition, it mediated interaction to the G-protein binding pocket (DRSmotif) and the DPxxY motif through interactions with residues of TM3 andwater mediated hydrogen bonds respectfully. The resulting active GnRH1Rconformation exhibited an open G-protein binding pocket, an enlarged ligandbinding pocket and key rearrangements of the DPxxY motif indicative ofactivation. Communication between GnRH1R and lipid molecules was also observed. The significance of this work transcends the confines of GnRH1R,contributing essential knowledge to the broader field of GPCR biology andcomputational studies. The identified binding mechanism and proposedinterhelical communication networks offer valuable insights for drug designtargeting GnRH1R, with implications for developing more precisetherapeutics for reproductive system-related disorders. Finally, the details ofthe discovered communication pathways initiated by GnRH pave the way fora deeper understanding of GPCR activation.
- Advisor / supervisor
- Ferro, Valerie
- Mulheran, Paul
- Resource Type
- DOI
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PDF of thesis T17138 | 2024-10-23 | Public | Download |