DC 12: Characterization of RNA-ligand interactions using X-ray crystallography and other biophysical methods
Research field: structural biology, biophysics.
PhD project description:
The PhD project will focus on the characterization of RNA-ligand interactions using X-ray crystallography and other biophysical methods to underpin the design of potent RNA-ligands for various targets. In addition, you will also carry out fragment screening using X-ray crystallography to discover new RNA-ligands that can be optimized into compounds with antibiotic activity.
In one part of the work, you will focus on obtaining crystals of the FMN, SAM-III and SAM-I/IV riboswitches suitable for soaking ligands at high concentrations. For this, you will make use of technology developed at CrystalsFirst. CrystalsFirst’s SmartSoak-technology offers a rational process to determine conditions in which macromolecular crystals are stable against the exposure to organic solvents and cryo-protection. Based on these conditions, soaking systems amenable to high concentrations of ligands and long soaking times can be proposed, usually leading to a higher success rate and better resolution than commonly used approaches of trial and error. Subsequently, the established conditions will be used to conduct a fragment screen using X-ray crystallography for the SAM-III and SAM-I/IV riboswitches. In addition, the established conditions will also be used to soak fragment hits obtained in WP2 by other PhD candidates using other technologies. The obtained structures will be fed into WP2 as basis for compound design. Likewise, co-crystal structures of the FMN, SAM-III and SAM-I/IV riboswitches with ligands synthesized in WP2 will be determined to support optimization.
Further, you will determine binding affinities and binding kinetics of compounds from WP2 for all riboswitches that the consortium will work on and the 5’-UTR of ompA using surface plasmon resonance (SPR). In addition, for selected ligands, you will determine thermodynamic parameters using isothermal titration calorimetry (ITC) to underpin structure-activity relationships (SAR).
Research environment:
You will work in a team together with other PhD students and postdocs, both within the TargetRNA doctoral network, the research group, and at CrystalsFirst. The work tasks will be varied, and you will learn a range of biophysical methods to characterize RNA-ligand binding, but also binding of small molecules to macromolecules more generally.
The PhD position is associated to the Brenk lab, which is part of the research unit for Structural biology and drug discovery
Skills/qualifications:
• Applicants must hold a master's degree or equivalent education in pharmacy, biochemistry, molecular biology, biophysics, or a related discipline. The master's degree has to be equivalent to a five-years master's degree obtained in Norway. Master students can apply provided they complete their final master exam before 01.11.2024. It is a condition of employment that the master's degree has been awarded.
• Applicants must have a documented solid practical and theoretical background within X-ray crystallography or other biophysical methods relevant for the project (SPR, ITC, or related methods)
• Experience with sample preparation for biophysical experiments (X-ray crystallography, SPR, ITC, or related methods) is required
• Experience with in vitro transcription of RNA is an advantage
• The candidate must demonstrate a strong commitment and enthusiasm for the characterization of RNA-ligand interactions and for research in the TargetRNA network in general
• The candidate must be able to work independently and interactively in a team setting.
• A structured approach to work and excellent communication skills and fluency in both written and spoken English are required
Personal and relational qualities will be emphasized. Ambitions and potential will also count when evaluating the candidates.
Organized research training (PhD program): The candidate must take part in the University of Bergen approved PhD programme leading to the degree within a time limit of 3 years. You must have admission to the organized research training (PhD program, see the reqirements here) at the Faculty in order to qualify for the position. Application for admission to the PhD programme, including a project plan outline for the training plan must be submitted no later than three months after the date of commencement.
The PhD-position: PhD-positions are fixed term positions. You cannot be employed in a PhD-position for more than one fixed term period at the same institution or have had similar employment at an institution in the region.
The University of Bergen is subjected to the regulation for export control system. The regulation will be applied in the processing of the applications. The University of Bergen applies the principle of public access to information when recruiting staff for academic positions.
Benefits/salary/social security:
• Exciting development opportunities as part of your role in a strong professional environment.
• Salary at pay grade 55 (code 1017/pay framework 20.10) NOK 540 500 before taxes, in the state scales. Further increases in salary will be based on seniority in the position.
• Enrolment in the Norwegian Public Service Pension Fund.
• Good welfare benefits.
State employment shall reflect the diversity of Norwegian society to the greatest extent possible. People with immigrant backgrounds and people with disabilities are encouraged to apply for the position. The University of Bergen applies the principle of public access to information when recruiting staff for academic positions. Information about applicants may be made public even if the applicant has asked not to be named on the list of persons who have applied. The applicant must be notified if the request is not met. Further information about our employment process can be found here.
For more information about the position, please contact Ruth Brenk.
Supervisor: Ruth Brenk.
Host institute: Department of Biomedicine, University of Bergen, Norway.
Secondments planned: CrystalsFirst, supervisor Glinca, establishment of conditions to obtain stable crystals for soaking at high concentration, fragment screening (12 months).
Doctoral program: Doctoral education at the Faculty of Medicine, University of Bergen. Doctoral education at the Faculty of Medicine | Faculty of Medicine | UiB
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