{"entity": "researcher", "timestamp": "2026-07-19T07:05:56.031Z", "family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "affiliations": ["BioMS-Swedish National Infrastructure for Biological Mass Spectrometry, Lund University, Lund, Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347"}}, "publications": [{"entity": "publication", "iuid": "6dfc892282ff426f998cbc7c26e3828f", "links": {"self": {"href": "https://publications.scilifelab.se/publication/6dfc892282ff426f998cbc7c26e3828f.json"}, "display": {"href": "https://publications.scilifelab.se/publication/6dfc892282ff426f998cbc7c26e3828f"}}, "title": "The N-Myc MB0-MBI region interacts specifically and dynamically with the N-lobe of Aurora kinase A.", "authors": [{"family": "Hultman", "given": "Johanna", "initials": "J", "orcid": "0009-0000-8066-228X", "researcher": {"href": "https://publications.scilifelab.se/researcher/cd75d9341822427db7b8b8b8510123fd.json"}}, {"family": "Morad", "given": "Vivian", "initials": "V", "orcid": "0000-0001-9665-4532", "researcher": {"href": "https://publications.scilifelab.se/researcher/36505a4d209d4f439785a062205b180c.json"}}, {"family": "Tanner", "given": "Eliane", "initials": "E"}, {"family": "Kenney", "given": "Tristan M G", "initials": "TMG", "orcid": "0000-0001-8242-4349", "researcher": {"href": "https://publications.scilifelab.se/researcher/b739b627992645428ea12ed180dab914.json"}}, {"family": "Pietras", "given": "Zuzanna", "initials": "Z", "orcid": "0000-0002-4501-7311", "researcher": {"href": "https://publications.scilifelab.se/researcher/973d7a63037c432db0f7ca9607b8525b.json"}}, {"family": "Khare", "given": "Lalit Pramod", "initials": "LP"}, {"family": "Derbyshire", "given": "Dean", "initials": "D"}, {"family": "Resetca", "given": "Diana", "initials": "D"}, {"family": "Arrowsmith", "given": "Cheryl H", "initials": "CH"}, {"family": "Aili", "given": "Daniel", "initials": "D", "orcid": "0000-0002-7001-9415", "researcher": {"href": "https://publications.scilifelab.se/researcher/cc760610215a4dee9061f28723b97e62.json"}}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}}, {"family": "Penn", "given": "Linda Z", "initials": "LZ", "orcid": "0000-0001-8133-5459", "researcher": {"href": "https://publications.scilifelab.se/researcher/780529b33355480890244ff1039ea64f.json"}}, {"family": "Wallner", "given": "Bj\u00f6rn", "initials": "B", "orcid": "0000-0002-3772-8279", "researcher": {"href": "https://publications.scilifelab.se/researcher/108086b7b06e4247b332ff4a119b97a5.json"}}, {"family": "Ahlner", "given": "Alexandra", "initials": "A", "orcid": "0000-0001-7004-8251", "researcher": {"href": "https://publications.scilifelab.se/researcher/08cd17a1108045b5be32cd492a082453.json"}}, {"family": "Sunnerhagen", "given": "Maria", "initials": "M", "orcid": "0000-0002-0492-5890", "researcher": {"href": "https://publications.scilifelab.se/researcher/3caade7942f84928b12656cb7e5f8493.json"}}], "type": "journal article", "published": "2026-02-24", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "17", "issue": "1", "issn-l": "2041-1723"}, "abstract": "The intrinsically disordered MYC proteins are master regulators of cellular growth and function, but when deregulated they become cancer drivers. MYC-protein interactions are key to oncogenesis, and while disrupting such interactions would be of significant therapeutic benefit, the intrinsically disordered properties of MYC have dramatically hampered their characterization. Here, we apply an integrated structural biology approach to describe the structure and dynamics of the N-Myc-Aurora A complex, which is critical in neuroendocrine tumor progression. We reveal a functional interaction where multiple binding sites on N-Myc interact with the Aurora A N-lobe. The interaction is governed by aromatic clusters within the conserved MB0 and MBI motifs in N-Myc that interact with Aurora A in a dynamic binding mode that allosterically promotes kinase activation. We show that N-Myc binding to the Aurora A N-lobe can be inhibited by the small-molecule AurkinA, providing opportunity for therapeutical strategies to disrupt this interaction.", "doi": "10.1038/s41467-026-69725-1", "pmid": "41735282", "labels": {"Structural Proteomics": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC12936163"}, {"db": "pii", "key": "10.1038/s41467-026-69725-1"}], "notes": [], "created": "2026-04-07T14:24:57.298Z", "modified": "2026-04-07T14:24:58.191Z"}, {"entity": "publication", "iuid": "3fe1414d1f404aa7868cec9204360adb", "links": {"self": {"href": "https://publications.scilifelab.se/publication/3fe1414d1f404aa7868cec9204360adb.json"}, "display": {"href": "https://publications.scilifelab.se/publication/3fe1414d1f404aa7868cec9204360adb"}}, "title": "Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15", "authors": [{"family": "Ebenwaldner", "given": "Carmen", "initials": "C", "orcid": "0000-0002-7919-2994", "researcher": {"href": "https://publications.scilifelab.se/researcher/e2aedf9747ff49eb904e353f28847b61.json"}}, {"family": "Garc\u00eda Saura", "given": "Antonio Gin\u00e9s", "initials": "AG"}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}}, {"family": "Bernfur", "given": "Katja", "initials": "K", "orcid": "0000-0002-7927-9563", "researcher": {"href": "https://publications.scilifelab.se/researcher/4600cd5ea61b41e4ab9b85af90fb41b4.json"}}, {"family": "Moche", "given": "Martin", "initials": "M"}, {"family": "Logan", "given": "Derek T", "initials": "DT", "orcid": "0000-0002-0098-8560", "researcher": {"href": "https://publications.scilifelab.se/researcher/da2734243cdb4142be696e5a82e788ae.json"}}, {"family": "Cohen", "given": "Michael S", "initials": "MS", "orcid": "0000-0002-7636-4156", "researcher": {"href": "https://publications.scilifelab.se/researcher/352749e458584319ab9d870abec5d90f.json"}}, {"family": "Sch\u00fcler", "given": "Herwig", "initials": "H", "orcid": "0000-0003-4059-3501", "researcher": {"href": "https://publications.scilifelab.se/researcher/f49b25ddfc934f3ca41020c3f38c6bfc.json"}}], "type": "journal-article", "published": "2025-10-29", "journal": {"title": "Nat Commun", "issn": "2041-1723", "issn-l": "2041-1723", "volume": "16", "issue": "1", "pages": null}, "abstract": null, "doi": "10.1038/s41467-025-65315-9", "pmid": null, "labels": {"Structural Proteomics": "Collaborative"}, "xrefs": [], "notes": [], "created": "2024-11-27T17:26:39.850Z", "modified": "2025-11-26T16:30:32.588Z"}, {"entity": "publication", "iuid": "4511a6759a1f496e8c06555aa49190df", "links": {"self": {"href": "https://publications.scilifelab.se/publication/4511a6759a1f496e8c06555aa49190df.json"}, "display": {"href": "https://publications.scilifelab.se/publication/4511a6759a1f496e8c06555aa49190df"}}, "title": "Design of a Streptolysin O Epitope-Centric Nanoparticle Vaccine Against Streptococcus pyogenes", "authors": [{"family": "Tang", "given": "Di", "initials": "D", "orcid": "0000-0001-6323-9375", "researcher": {"href": "https://publications.scilifelab.se/researcher/e2a27467c4094d9f8d8f8402efa333f4.json"}}, {"family": "Chao", "given": "Yashuan", "initials": "Y", "orcid": "0000-0002-0295-3142", "researcher": {"href": "https://publications.scilifelab.se/researcher/ed7bd7c821754977ba516c3e1c04eceb.json"}}, {"family": "Hjortswang", "given": "Elisabeth", "initials": "E", "orcid": "0009-0003-9932-1751", "researcher": {"href": "https://publications.scilifelab.se/researcher/2fcf5002d49b458f81cea775594e63fb.json"}}, {"family": "Str\u00f6baek", "given": "Joel", "initials": "J", "orcid": "0000-0003-1231-0420", "researcher": {"href": "https://publications.scilifelab.se/researcher/c8d9f6cfe0e845d0a4208d442e4b652c.json"}}, {"family": "Hultgren", "given": "Lucas", "initials": "L"}, {"family": "Mohanty", "given": "Tirthankar", "initials": "T", "orcid": "0000-0003-4593-9612", "researcher": {"href": "https://publications.scilifelab.se/researcher/0a9c51697d33414f8197c7833d9dcc04.json"}}, {"family": "Karlsson", "given": "Christofer", "initials": "C", "orcid": "0000-0002-7099-0092", "researcher": {"href": "https://publications.scilifelab.se/researcher/ef353abbc90943218c194ccdd2bbdb52.json"}}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Shannon", "given": "Oonagh", "initials": "O", "orcid": "0000-0001-8291-8189", "researcher": {"href": "https://publications.scilifelab.se/researcher/ed4685bab7584028a070fc5a829bd386.json"}}, {"family": "Malmstr\u00f6m", "given": "Lars", "initials": "L"}, {"family": "Malmstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad3c999da10c41e4a3afda2718815083.json"}}], "type": "posted-content", "published": "2025-05-28", "journal": {"title": "biorxiv", "issn": null, "issn-l": null, "volume": null, "issue": null, "pages": null}, "abstract": null, "doi": "10.1101/2025.05.25.655993", "pmid": null, "labels": {"Cryo-EM": "Service"}, "xrefs": [], "notes": [], "created": "2025-11-13T14:22:08.439Z", "modified": "2025-12-18T19:15:21.994Z"}, {"entity": "publication", "iuid": "c99bc8e1a31143e2bd7fd1ef3ba8ab01", "links": {"self": {"href": "https://publications.scilifelab.se/publication/c99bc8e1a31143e2bd7fd1ef3ba8ab01.json"}, "display": {"href": "https://publications.scilifelab.se/publication/c99bc8e1a31143e2bd7fd1ef3ba8ab01"}}, "title": "Dissecting the properties of circulating IgG against streptococcal pathogens through a combined systems antigenomics-serology workflow", "authors": [{"family": "Gomez Toledo", "given": "Alejandro", "initials": "A", "orcid": "0000-0002-2103-7158", "researcher": {"href": "https://publications.scilifelab.se/researcher/9e9d9a5e2dc148c9bcdc07f2b4a17ebc.json"}}, {"family": "Chowdhury", "given": "Sounak", "initials": "S"}, {"family": "Hjortswang", "given": "Elisabeth", "initials": "E", "orcid": "0009-0003-9932-1751", "researcher": {"href": "https://publications.scilifelab.se/researcher/2fcf5002d49b458f81cea775594e63fb.json"}}, {"family": "Sorrentino", "given": "James T", "initials": "JT"}, {"family": "Lewis", "given": "Nathan E", "initials": "NE", "orcid": "0000-0001-7700-3654", "researcher": {"href": "https://publications.scilifelab.se/researcher/f8b8fb6dee874a178dd5c9d10d280982.json"}}, {"family": "Bl\u00e4ckberg", "given": "Anna", "initials": "A"}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}}, {"family": "Kjellstr\u00f6m", "given": "Sven", "initials": "S", "orcid": "0000-0003-4646-5279", "researcher": {"href": "https://publications.scilifelab.se/researcher/dfae5f64ec9d45e282cdfd038539fe25.json"}}, {"family": "Izadi", "given": "Arman", "initials": "A", "orcid": "0000-0002-0262-1017", "researcher": {"href": "https://publications.scilifelab.se/researcher/2d6f1927cfc643818a0a3a1b8602af14.json"}}, {"family": "Olofsson", "given": "Berit", "initials": "B", "orcid": "0009-0009-0602-2183", "researcher": {"href": "https://publications.scilifelab.se/researcher/9ad483473b044b7dbc7e6c61ef1c0a73.json"}}, {"family": "Nordenfelt", "given": "Pontus", "initials": "P", "orcid": "0000-0002-9481-9951", "researcher": {"href": "https://publications.scilifelab.se/researcher/7aa3418ab23a4ec48c037d6d6ddea5b5.json"}}, {"family": "Malmstr\u00f6m", "given": "Lars", "initials": "L", "orcid": "0000-0001-9885-9312", "researcher": {"href": "https://publications.scilifelab.se/researcher/42e99f34fb854beb8d810b05fe941057.json"}}, {"family": "Rasmussen", "given": "Magnus", "initials": "M"}, {"family": "Malmstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad3c999da10c41e4a3afda2718815083.json"}}], "type": "journal-article", "published": "2025-02-24", "journal": {"title": "Nat Commun", "issn": "2041-1723", "issn-l": "2041-1723", "volume": "16", "issue": "1", "pages": null}, "abstract": null, "doi": "10.1038/s41467-025-57170-5", "pmid": null, "labels": {"Structural Proteomics": "Collaborative"}, "xrefs": [], "notes": [], "created": "2023-12-01T13:27:44.561Z", "modified": "2025-03-24T08:20:48.298Z"}, {"entity": "publication", "iuid": "be1ccad457054a6ca82002c69b0dacdb", "links": {"self": {"href": "https://publications.scilifelab.se/publication/be1ccad457054a6ca82002c69b0dacdb.json"}, "display": {"href": "https://publications.scilifelab.se/publication/be1ccad457054a6ca82002c69b0dacdb"}}, "title": "Streptolysin O accelerates the conversion of plasminogen to plasmin", "authors": [{"family": "Tang", "given": "Di", "initials": "D", "orcid": "0000-0001-6323-9375", "researcher": {"href": "https://publications.scilifelab.se/researcher/e2a27467c4094d9f8d8f8402efa333f4.json"}}, {"family": "Khakzad", "given": "Hamed", "initials": "H", "orcid": "0000-0002-8556-0650", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7b030c1452c4dc9b430deffdf493e6f.json"}}, {"family": "Hjortswang", "given": "Elisabeth", "initials": "E"}, {"family": "Malmstr\u00f6m", "given": "Lars", "initials": "L", "orcid": "0000-0001-9885-9312", "researcher": {"href": "https://publications.scilifelab.se/researcher/42e99f34fb854beb8d810b05fe941057.json"}}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Malmstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad3c999da10c41e4a3afda2718815083.json"}}], "type": "journal-article", "published": "2024-11-25", "journal": {"title": "Nat Commun", "issn": "2041-1723", "issn-l": "2041-1723", "volume": "15", "issue": "1", "pages": "10212"}, "abstract": "Group A Streptococcus (GAS) is a human-specific bacterial pathogen that can exploit the plasminogen-plasmin fibrinolysis system to dismantle blood clots and facilitate its spread and survival within the human host. In this study, we use affinity-enrichment mass spectrometry to decipher the host-pathogen protein-protein interaction between plasminogen and streptolysin O, a key cytolytic toxin produced by GAS. This interaction accelerates the conversion of plasminogen to plasmin by both the host tissue-type plasminogen activator and streptokinase, a bacterial plasminogen activator secreted by GAS. Integrative structural mass spectrometry analysis shows that the interaction induces local conformational shifts in plasminogen. These changes lead to the formation of a stabilised intermediate plasminogen-streptolysin O complex that becomes significantly more susceptible to proteolytic processing by plasminogen activators. Our findings reveal a conserved and moonlighting pathomechanistic function for streptolysin O that extends beyond its well-characterised cytolytic activity.", "doi": "10.1038/s41467-024-54173-6", "pmid": "39587097", "labels": {"Structural Proteomics": "Technology development"}, "xrefs": [{"db": "pii", "key": "10.1038/s41467-024-54173-6"}, {"db": "pmc", "key": "PMC11589678"}], "notes": [], "created": "2024-11-27T17:20:53.877Z", "modified": "2024-11-28T17:40:23.904Z"}, {"entity": "publication", "iuid": "3100faff46cb445d8dae8195bbe80fb2", "links": {"self": {"href": "https://publications.scilifelab.se/publication/3100faff46cb445d8dae8195bbe80fb2.json"}, "display": {"href": "https://publications.scilifelab.se/publication/3100faff46cb445d8dae8195bbe80fb2"}}, "title": "Nucleotide binding to the ATP-cone in anaerobic ribonucleotide reductases allosterically regulates activity by modulating substrate binding", "authors": [{"family": "Bimai", "given": "Ornella", "initials": "O", "orcid": "0000-0003-0562-7251", "researcher": {"href": "https://publications.scilifelab.se/researcher/9545ade4d51c4c4089d97eb74841deec.json"}}, {"family": "Banerjee", "given": "Ipsita", "initials": "I"}, {"family": "Rozman Grinberg", "given": "Inna", "initials": "I", "orcid": "0000-0003-3094-1998", "researcher": {"href": "https://publications.scilifelab.se/researcher/2d4a64db2f9544b2bde744b063dc5247.json"}}, {"family": "Huang", "given": "Ping", "initials": "P", "orcid": "0000-0002-7676-6905", "researcher": {"href": "https://publications.scilifelab.se/researcher/f6e89aa29dfb4e06bd4c1530183dd8fb.json"}}, {"family": "Hultgren", "given": "Lucas", "initials": "L"}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}}, {"family": "Lundin", "given": "Daniel", "initials": "D", "orcid": "0000-0002-8779-6464", "researcher": {"href": "https://publications.scilifelab.se/researcher/227cc90e084348a193fee05eb23a6bf3.json"}}, {"family": "Sj\u00f6berg", "given": "Britt Marie", "initials": "BM", "orcid": "0000-0001-5953-3360", "researcher": {"href": "https://publications.scilifelab.se/researcher/fab276f213364c2eaa6fe3dc5c9b01ff.json"}}, {"family": "Logan", "given": "Derek T", "initials": "DT", "orcid": "0000-0002-0098-8560", "researcher": {"href": "https://publications.scilifelab.se/researcher/da2734243cdb4142be696e5a82e788ae.json"}}], "type": "journal-article", "published": "2024-07-05", "journal": {"title": "Elife", "issn": "2050-084X", "issn-l": "2050-084X", "volume": "12", "issue": null, "pages": null}, "abstract": null, "doi": "10.7554/elife.89292.4", "pmid": null, "labels": {"Cryo-EM": "Service", "Structural Proteomics": "Service"}, "xrefs": [], "notes": [], "created": "2023-11-26T08:28:54.746Z", "modified": "2025-10-25T10:14:48.910Z"}, {"entity": "publication", "iuid": "58ed0fc0d058426ca2f18b39c8fdd6bb", "links": {"self": {"href": "https://publications.scilifelab.se/publication/58ed0fc0d058426ca2f18b39c8fdd6bb.json"}, "display": {"href": "https://publications.scilifelab.se/publication/58ed0fc0d058426ca2f18b39c8fdd6bb"}}, "title": "Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs.", "authors": [{"family": "Petruk", "given": "Ganna", "initials": "G", "orcid": "0000-0003-1336-2900", "researcher": {"href": "https://publications.scilifelab.se/researcher/496c3fa062e34cd2a92941720fe62b5a.json"}}, {"family": "Puthia", "given": "Manoj", "initials": "M", "orcid": "0000-0001-6048-7234", "researcher": {"href": "https://publications.scilifelab.se/researcher/f794b8d0d66a4bab964e915ff71a7023.json"}}, {"family": "Samsudin", "given": "Firdaus", "initials": "F"}, {"family": "Petrlova", "given": "Jitka", "initials": "J", "orcid": "0000-0002-7554-3945", "researcher": {"href": "https://publications.scilifelab.se/researcher/8f5e9799bbd647309b383de9f754df00.json"}}, {"family": "Olm", "given": "Franziska", "initials": "F", "orcid": "0000-0001-5222-6130", "researcher": {"href": "https://publications.scilifelab.se/researcher/b5b929c8316a43b7938fbc6cd2bf330e.json"}}, {"family": "Mittendorfer", "given": "Margareta", "initials": "M"}, {"family": "Hyll\u00e9n", "given": "Snejana", "initials": "S", "orcid": "0000-0003-1253-4969", "researcher": {"href": "https://publications.scilifelab.se/researcher/2ce81a1e114d4de08470ee8c44d7e15d.json"}}, {"family": "Edstr\u00f6m", "given": "Dag", "initials": "D"}, {"family": "Str\u00f6mdahl", "given": "Ann-Charlotte", "initials": "AC"}, {"family": "Diehl", "given": "Carl", "initials": "C"}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}}, {"family": "Walse", "given": "Bj\u00f6rn", "initials": "B", "orcid": "0000-0003-1513-9040", "researcher": {"href": "https://publications.scilifelab.se/researcher/216f98091f43414eae8cd583dcd9a24d.json"}}, {"family": "Kjellstr\u00f6m", "given": "Sven", "initials": "S", "orcid": "0000-0003-4646-5279", "researcher": {"href": "https://publications.scilifelab.se/researcher/dfae5f64ec9d45e282cdfd038539fe25.json"}}, {"family": "Bond", "given": "Peter J", "initials": "PJ", "orcid": "0000-0003-2900-098X", "researcher": {"href": "https://publications.scilifelab.se/researcher/34efd0fc1d104a839dced094addd4d91.json"}}, {"family": "Lindstedt", "given": "Sandra", "initials": "S"}, {"family": "Schmidtchen", "given": "Artur", "initials": "A", "orcid": "0000-0001-9209-3141", "researcher": {"href": "https://publications.scilifelab.se/researcher/406510dc3844487e9c45f713ea173b8e.json"}}], "type": "journal article", "published": "2023-09-29", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "14", "issue": "1", "pages": "6097", "issn-l": "2041-1723"}, "abstract": "There is a clinical need for conceptually new treatments that target the excessive activation of inflammatory pathways during systemic infection. Thrombin-derived C-terminal peptides (TCPs) are endogenous anti-infective immunomodulators interfering with CD14-mediated TLR-dependent immune responses. Here we describe the development of a peptide-based compound for systemic use, sHVF18, expressing the evolutionarily conserved innate structural fold of natural TCPs. Using a combination of structure- and in silico-based design, nuclear magnetic resonance spectroscopy, biophysics, mass spectrometry, cellular, and in vivo studies, we here elucidate the structure, CD14 interactions, protease stability, transcriptome profiling, and therapeutic efficacy of sHVF18. The designed peptide displays a conformationally stabilized, protease resistant active innate fold and targets the LPS-binding groove of CD14. In vivo, it shows therapeutic efficacy in experimental models of endotoxin shock in mice and pigs and increases survival in mouse models of systemic polymicrobial infection. The results provide a drug class based on Nature\u00b4s own anti-infective principles.", "doi": "10.1038/s41467-023-41702-y", "pmid": "37773180", "labels": {"Clinical Genomics Lund": "Service", "Structural Proteomics": "Collaborative", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC10541425"}, {"db": "pii", "key": "10.1038/s41467-023-41702-y"}], "notes": [], "created": "2023-11-21T18:39:47.348Z", "modified": "2023-12-01T13:27:00.432Z"}, {"entity": "publication", "iuid": "4d4e2e80bfcf4d0781b374cc3b7fe44e", "links": {"self": {"href": "https://publications.scilifelab.se/publication/4d4e2e80bfcf4d0781b374cc3b7fe44e.json"}, "display": {"href": "https://publications.scilifelab.se/publication/4d4e2e80bfcf4d0781b374cc3b7fe44e"}}, "title": "Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome.", "authors": [{"family": "Guzzi", "given": "Nicola", "initials": "N"}, {"family": "Muthukumar", "given": "Sowndarya", "initials": "S", "orcid": "0000-0002-9110-722X", "researcher": {"href": "https://publications.scilifelab.se/researcher/b65fac156e66450a84e01599b363f3c0.json"}}, {"family": "Cie\u015bla", "given": "Maciej", "initials": "M"}, {"family": "Todisco", "given": "Gabriele", "initials": "G", "orcid": "0000-0001-6583-3829", "researcher": {"href": "https://publications.scilifelab.se/researcher/0bdb2b7dcd8a4fa497748ee5e165f11e.json"}}, {"family": "Ngoc", "given": "Phuong Cao Thi", "initials": "PCT", "orcid": "0000-0002-3059-9179", "researcher": {"href": "https://publications.scilifelab.se/researcher/40df589d51ca4406ad49a152c9c9baeb.json"}}, {"family": "Madej", "given": "Magdalena", "initials": "M", "orcid": "0000-0003-3821-3514", "researcher": {"href": "https://publications.scilifelab.se/researcher/19286e6584f44a23be68dcb7811b200f.json"}}, {"family": "Munita", "given": "Roberto", "initials": "R"}, {"family": "Fazio", "given": "Serena", "initials": "S"}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}}, {"family": "Mortera-Blanco", "given": "Teresa", "initials": "T"}, {"family": "Jansson", "given": "Monika", "initials": "M"}, {"family": "Nannya", "given": "Yasuhito", "initials": "Y"}, {"family": "Cazzola", "given": "Mario", "initials": "M", "orcid": "0000-0001-6984-8817", "researcher": {"href": "https://publications.scilifelab.se/researcher/e85ab5f89c604aad824a42107184f196.json"}}, {"family": "Ogawa", "given": "Seishi", "initials": "S"}, {"family": "Malcovati", "given": "Luca", "initials": "L", "orcid": "0000-0002-1460-1611", "researcher": {"href": "https://publications.scilifelab.se/researcher/ac37858898774ff29209add33a79fd48.json"}}, {"family": "Hellstr\u00f6m-Lindberg", "given": "Eva", "initials": "E", "orcid": "0000-0002-7839-3743", "researcher": {"href": "https://publications.scilifelab.se/researcher/6bf8d52e24234fa8b348ad08f58d1d48.json"}}, {"family": "Dimitriou", "given": "Marios", "initials": "M", "orcid": "0000-0001-8362-2099", "researcher": {"href": "https://publications.scilifelab.se/researcher/531c153359bb400fb48c7324a3bd69ad.json"}}, {"family": "Bellodi", "given": "Cristian", "initials": "C", "orcid": "0000-0001-8047-5329", "researcher": {"href": "https://publications.scilifelab.se/researcher/96cf2b32e6804ebb848bb3fc6af41e4c.json"}}], "type": "journal article", "published": "2022-03-00", "journal": {"title": "Nat Cell Biol", "issn": "1476-4679", "volume": "24", "issue": "3", "pages": "299-306", "issn-l": null}, "abstract": "Transfer RNA-derived fragments (tRFs) are emerging small noncoding RNAs that, although commonly altered in cancer, have poorly defined roles in tumorigenesis1. Here we show that pseudouridylation (\u03a8) of a stem cell-enriched tRF subtype2, mini tRFs containing a 5' terminal oligoguanine (mTOG), selectively inhibits aberrant protein synthesis programmes, thereby promoting engraftment and differentiation of haematopoietic stem and progenitor cells (HSPCs) in patients with myelodysplastic syndrome (MDS). Building on evidence that mTOG-\u03a8 targets polyadenylate-binding protein cytoplasmic 1 (PABPC1), we employed isotope exchange proteomics to reveal critical interactions between mTOG and functional RNA-recognition motif (RRM) domains of PABPC1. Mechanistically, this hinders the recruitment of translational co-activator PABPC1-interacting protein 1 (PAIP1)3 and strongly represses the translation of transcripts sharing pyrimidine-enriched sequences (PES) at the 5' untranslated region (UTR), including 5' terminal oligopyrimidine tracts (TOP) that encode protein machinery components and are frequently altered in cancer4. Significantly, mTOG dysregulation leads to aberrantly increased translation of 5' PES messenger RNA (mRNA) in malignant MDS-HSPCs and is clinically associated with leukaemic transformation and reduced patient survival. These findings define a critical role for tRFs and \u03a8 in difficult-to-treat subsets of MDS characterized by high risk of progression to acute myeloid leukaemia (AML).", "doi": "10.1038/s41556-022-00852-9", "pmid": "35292784", "labels": {"Structural Proteomics": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1038/s41556-022-00852-9"}, {"db": "pmc", "key": "PMC8924001"}], "notes": [], "created": "2022-04-27T14:24:05.670Z", "modified": "2022-04-27T14:24:05.913Z"}]}