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Within families such as MAX, LARS and RALPH effectors, individual proteins maintain nearly identical three\u2010dimensional 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\u2013function 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\u2010host interactions, frustration\u2010guided 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\u2010driven protein design for developing broad\u2010spectrum resistance against major classes of plant pathogen effectors.<\/jats:p>","DOI":"10.1111\/tpj.70971","type":"journal-article","created":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T20:54:52Z","timestamp":1780779292000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["How to frustrate a plant pathogen"],"prefix":"10.1111","volume":"126","author":[{"given":"Gregory","family":"Knight","sequence":"first","affiliation":[{"name":"Centre for Programmable Biological Matter, Department of Biosciences Durham University  Durham DH1 3LE UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Heddle","sequence":"additional","affiliation":[{"name":"Centre for Programmable Biological Matter, Department of Biosciences Durham University  Durham DH1 3LE UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5906-0962","authenticated-orcid":false,"given":"Adam R.","family":"Bentham","sequence":"additional","affiliation":[{"name":"Centre for Programmable Biological Matter, Department of Biosciences Durham University  Durham DH1 3LE UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,6]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btab329"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/plcell\/koad204"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV120.010852"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009957"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1094\/MPMI\u201008\u201023\u20100118\u2010FI"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/tpj.12913"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10311"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914408107"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.262303"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2307604120"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201019560\u20109"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbi.2023.102402"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.01774\u201021"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.10856"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005228"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.00644"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201040949\u20109"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.7b07363"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2812"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens11050583"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2017.09.006"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2018.01.020"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1128\/mmbr.00066\u201016"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201043801\u20102"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.0c11068"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20220059"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/mpp.13315"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1819481116"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xplc.2020.100050"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010023\u201000673\u20100"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05286"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/tpj.13780"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1105\/tpc.113.120055"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44222\u2010025\u201000349\u20108"},{"key":"e_1_2_12_36_1","unstructured":"Kyro G.W. 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