PhD Studentship: AI-designed effector minibinders for suppression of fungal plant pathogens

Fungal pathogens are expert manipulators of their plant hosts, which is achieved through the activity of secreted effector proteins which disable plant immunity. Understanding effector function has been enhanced through predictive structural biology tools such as AlphaFold, which allow accurate prediction of effector structures from primary sequence. We recently identified a number of immune-suppressing effectors from the major wheat pathogen Zymoseptoria tritici. These effectors have diverse phenotypes when expressed in plants and many have high-confidence AlphaFold predictions.

This project aims to use the most recent advances in AI-guided structural biology to design artificial protein minibinders that are able to bind specifically and inactivate secreted fungal effector proteins. The student will be responsible for designing protein minibinders using pipelines such as RFdiffusion, BindCraft and Latent-X. These will be designed against a panel of Z. tritici effectors with confirmed or high-confidence structures. Minibinders and effectors will be produced in heterologous expression systems and purified by affinity chromatography. Pairwise interactions between effectors and minibinders will be tested by isothermal titration calorimetry (ITC) or microscale thermophoresis (MST) in collaboration with the lab of Prof. Andy Lovering. In parallel, minibinder/effector pairs will be co-expressed using Agrobacterium-mediated transient expression in Nicotiana benthamiana. This will test whether minibinders are able to disrupt and ameliorate the known phenotypes of their target effector. We anticipate that the highest affinity minibinders will be both detectable by ITC/MST and modify effector phenotypes in plants. If successful, this will be the proof-of-concept that in-silico designed minibinders can interact with pathogen effectors and suppress their activity.

For informal enquiries, please contact Dr Graeme Kettles at g.j.kettles@bham.ac.uk.

Funding notes:

This is a PhD studentship with the Midlands Integrated Biosciences Training Partnership, funded by BBSRC and in partnership with the University of Warwick, Aston University, Harper Adams University, Coventry University, and the University of Leicester.
For more details please visit: https://warwick.ac.uk/fac/cross_fac/mibtp/ or https://www.birmingham.ac.uk/about/college-of-life-and-environmental-sciences/midlands-integrative-biosciences-training-partnership

References:
Thynne E, et al. An array of Zymoseptoria tritici effectors suppress plant immune responses. Mol Plant Pathol. 2024 Oct;25(10):e13500. doi: 10.1111/mpp.13500. PMID: 39394693; PMCID: PMC11470090.

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