How to frustrate a plant pathogen.

Sequence-unrelated but structurally similar (SUSS) effector families represent a distinctive evolutionary strategy among plant pathogen virulence proteins. Within families such as MAX, LARS and RALPH effectors, individual proteins maintain nearly identical three-dimensional folds despite minimal sequence identities, whilst targeting functionally diverse host cellular processes. This decoupling of structural conservation from functional specificity challenges traditional precepts of the classic structure-function paradigm and reveals how pathogen effectors exploit stable protein scaffolds as platforms for rapid functional diversification through extreme sequence variation. Comparative structural analyses suggest that surface frustration, regions of local energetic instability essential for fold flexibility, may be conserved across SUSS family members despite sequence divergence. This conservation creates potential vulnerabilities that could be exploited for resistance engineering. Rather than targeting individual effector-host interactions, frustration-guided design of molecular sponges, synthetic integrated domains or proteome degradation warheads could potentially neutralise entire SUSS effector families. This review explores the mechanisms of functionalisation by SUSS effectors and suggests strategies combining structural genomics, surface frustration analysis and AI-driven protein design for developing broad-spectrum resistance against major classes of plant pathogen effectors.