Computational design of novel β-catenin binders

1. Design strong and specific binders to the structured armadillo repeats in β-catenin, using templates based on models of IDR-β-catenin interactions (from DC#4).
2. Extend peptidic hits from WP2 and WP3 with non-peptidic modification to increase their potency.
3. Design minibinders to specific IDR regions in β-catenin.

Project Overview: The aim of this project is to design specific binders to β-catenin that can be used to modulate its activity. Starting from structural models of known interactions (from DC#4) and information from large-scale screens (DC#2, DC#3), we will calibrate a protocol to design binders to regions in the structured armadillo repeat of β-catenin, and to specific IDR regions in β-catenin that interact with partners. Designs will include PTM-specific binders that can be used to detect post-translational modifications (PTMs), and for the PTM-dependent modulation of β-catenin. We will start by applying and refining cutting-edge ML-based protocols for the generation of strong binders with a high rate of success (e.g., Bindcraft, Bindcraft2, BoltzGen, Frame2Seq, and more as they become available), similar to our design of a specific, strong binder to B55. We will also adapt our PatchMAN peptide docking protocol to identify good seed points for design. To derive sequence and structural requirements for specific β-catenin binding sites and resolve the impact of β-catenin PTMs (e.g., phosphorylation and methylation), we will include information from screens and MS experiments (Maric JMU, and Bonaldi UMI, WP2). In turn, we can extend initial hits (from proteomic screens, as well as from de novo designs) by using non-peptidic modifications to finetune state of the art ML protocols towards non-peptidic β-catenin binder identification and design. To target specific IDR regions of β-catenin we will start by following recent protocols by the Baker lab (de novo design with RFdiffusion and ProteinMPNN, or threading the target sequence onto a dedicated library of templates generated for peptide binding designs), and optimize a protocol to generate binders to specific IDRs in β-catenin. Together, we aim to develop a palette of inhibitors targeted to different regions in β-catenin, to allow for the detailed characterization of the role of these regions in function and disease (Abankwa, LUX, WP6&7). We will test binding using ITC (in-house), as well as use arrays (Maric, JMU, WP2) and structural characterization (Madl, MUG, WP4). These hits can then serve as starting points for further characterization in the other groups (WP 4).Contribution to the overall research program: High affinity, specific binders to β-catenin for targeted, site-specific modulation. To be used to decipher the functional roles of different regions in β-catenin.

Skills and research profile: Background in structural modelling and design using Deep Learning tools, and strong interest in combining computation with experiment. Collaborative spirit that will leverage input from the training network on the one hand, and provide binders for others in the network for the study of the functional regulation of and by βcatenin.

Salary: The position is funded by the Horizon Europe MSCA-DN project FlexCAT (Grant Agreement No. 101311592) for three years. The selected candidate will be offered a competitive salary comprising a Living Allowance (adjusted by the country correction coefficient), a Mobility Allowance, and, if applicable, a Family Allowance. All allowances are subject to applicable social security contributions and taxation.

Planned secondment: 1. Host: JMU; Supervisor: Dr. Hans Maric; Length: 2 months.

Purpose: Gaining experience in screens using non-canonical amino acids, to expand the diversity of identified peptidic binders.

Enrolment in Doctoral degree(s): HUJ (Schueler-Furman)

How to apply:
Applications are exclusively accepted through the Recruitment Portal (https://phdrecruiting.medunigraz.at/). The required information is specified in the recruitment portal and comprises:

• Motivation statement for selected DC projects
• Detailed CV; publication list if applicable
• BSc/MSc diplomas and academic transcripts/supplements
• Contact details for two referees

Applications will be assessed for eligibility and scientific/academic quality. Shortlisted applicants will be invited to interview. The final selection will follow the open, transparent and merit-based recruitment principles of MSCA.

Key dates:

• Applications open: 15 September 2026
• Applications close: 31 October 2026
• Online pre-interviews: early November 2026
• Final interviews: late November/early December 2026
• Decisions and offers: mid-December 2026
• Start: January 2027 – March 2027

Data protection statement
The personal data you provide as part of your application will be processed for the purposes necessary to administer the recruitment and selection process for the Doctoral Candidate position(s) for which you apply within the FlexCAT Marie Skłodowska-Curie Doctoral Network (MSCA-DN). Access to your application will be restricted to individuals directly involved in the recruitment and selection process, including the recruiting beneficiary, members of the selection committee, and, where necessary, authorised representatives of the FlexCAT consortium. Personal data will be processed in accordance with the applicable data-protection legislation, including the General Data Protection Regulation (EU) 2016/679 (GDPR), and the privacy policies of the recruiting beneficiary. Statistics for project reporting will be provided in anonymised or appropriately aggregated form.

Where to apply

Website: https://phd-recruiting.medunigraz.at/

Requirements

Research Field: Chemistry
Education Level: Master Degree or equivalent

Skills/Qualifications

Applicants of any nationality are welcome to apply. To be eligible for recruitment as an MSCA Doctoral Candidate, applicants must fulfil the following criteria at the date of recruitment:

• Education – you do not hold a doctoral degree and hold (or will shortly complete) a science Master’s degree (see individual project requirements), with excellent results, qualifying you for admission to the doctoral program of the respective host institution. The successful candidate must fulfil the admission requirements of the respective doctoral programme and will be enrolled in a doctoral programme during the project.
• Mobility - you must not have resided or carried out your main activity (work, studies, etc.) in recruiting beneficiary’s country for more than 12 months during the 36 months before your recruitment. Compulsory national service, holidays/short stays and time spent obtaining refugee status under the Geneva Convention4 are not considered for this purpose.
• Language & communication – excellent command of spoken and written English (min. B2 level). Ability to communicate results clearly to diverse audiences, both in writing and verbally.
• Motivation – motivation for multidisciplinary, international doctoral research, hands-on experimental work, mandatory academic/industy secondment(s), to publish research findings in international journals, present results at conferences and contribute to project deliverables. Willingness to contribute to project network-wide activities, communication, training events, and dissemination efforts.
• Technical skills – specific to the individual DC project (see individual project descriptions).

Specific Requirements

Skills and research profile: Background in structural modelling and design using Deep Learning tools, and strong interest in combining computation with experiment. Collaborative spirit that will leverage input from the training network on the one hand, and provide binders for others in the network for the study of the functional regulation of and by βcatenin.

Languages: ENGLISH
Level: Excellent
Research Field: Chemistry
Years of Research Experience: 1 - 4

Additional Information

Selection process

Applications will be assessed for eligibility and scientific/academic quality. Shortlisted applicants will be invited to interview. The final selection will follow the open, transparent and merit-based recruitment principles of MSCA.

Website for additional job details: https://phd-recruiting.medunigraz.at/

Work Location(s)

Number of offers available: 1
Company/Institute: The Hebrew University of Jerusalem
Country: Israel
City: Jerusalem