Structural Biology and Biochemistry (SBB) Theme Seminar

Speaker 1: Shannon Jewel 

Title: Investigating the structural elements of NLRX1, a novel therapeutic target in Parkinson’s disease

Abstract: Inflammation, a driving force in neurodegenerative disease, is mediated by the NFκB pathway which is negatively regulated by NLRX1. NLRX1 protein expression is significantly decreased in Parkinson’s disease patients compared to healthy controls, suggesting a potentially protective role for NLRX1, and making it an attractive therapeutic target (unpublished results). However, only the LRR domain of NLRX1 (cNLRX1) has been crystalized (PDB:  3un9); the limited structural data acts as a significant barrier to structure-based drug discovery efforts. To address this, we used 3un9 and the AlphaFold model of NLRX1 to model the structure of full-length NLRX1 as a homo-6-mer. The model generated has allowed us to identify new ligand binding sites. We propose an RNA-binding site in the previously uncharacterized N terminus, explore an ATP binding domain in the N terminus, present the protein as a member of the AAA ATPase family and highlight further druggable binding sites. We investigate the interactions of NLRX1 with known agonists NX13, NX64-3 and LABP-72-38 and suggest the most likely ligand binding sites. Further, we have attempted the expression and purification of cNLRX1 to validate those ligand binding sites identified in silico through crystallographic studies. Current efforts towards this are still underway.

Biography:  Shannon obtained her Bachelors in Biochemistry (Honours) from Brock University, Canada in June 2017, where she investigated qsal-like bi- and tetra-coordinated spin crossover complexes. She continued her studies at Brock University and obtained a Masters in (Organic) Chemistry in June 2020 after synthesizing and investigating various phosphatidylinositol bolalipids with the aim of understanding mechanistic pathways of Sec14 and PIK1. She started her PhD at UQ in April 2021 and is supervised by Prof. Avril Robertson and Prof. David Ascher at SCMB with a focus on drug discovery for Parkinson’s Disease. Her project has covered a broad area of research including protein target validation, compound testing, protein modelling and purification, and chemical synthesis. Having completed her Progress Review 3, Shannon is in the final stages of her PhD and is looking forward to a future career in industry.

Speaker 2: Isaac Tucker

Title: In-Silico Investigation of Venom-Derived Acid-Sensing Ion Channel Modulators to Determine Mechanism of Action: Combining Molecular Dynamics and Structure Prediction

Abstract:  Acidosis, a condition marked by an abnormal increase in acidity levels, is implicated in a wide array of pathologies, ranging from generalised pain to neurological disorders and even stroke. During these events, Acid-Sensing Ion Channels (ASICs) are activated and trigger cell death cascades that are responsible for a large proportion of the deaths associated with these pathologies. This presentation delves into modulators of ASIC subtype 1a to understand the mechanism of action and provide insight into designing the next generation of modulators. Specifically, we investigated Hi1a, a bivalent peptide with numerous desirable therapeutic traits, namely irreversibility, selectivity, and inhibition, to determine how it elicits these unique characteristics and differs from other known modulators of this channel such as PcTx1, Mambalgin, and MitTx. In the absence of a crystal structure, we utilised a series of in-silico tools, such as structure prediction and molecular dynamics simulations, coupled to electrophysiology to elucidate its mechanism of action.

Biography: Isaac is a 3rd year PhD candidate from the King group at the Institute of Molecular Bioscience. He is currently investigating all aspects of venom-derived peptide therapeutics: from their discovery, to their production, and finally their delivery. Prior to starting his PhD, he worked as a specialist consultant investigating the translation of biotechnologies to industry applications. He has recently returned from a 10-month Fulbright exchange to MIT conducted as a part of his PhD, where he investigated novel delivery systems and routes of administration for peptide therapeutics. He is particularly interested in addressing gaps between academic leads for their translation to the clinic.

 Join us at the secret garden following the seminar, for a morning tea catered by the Kobe lab.