{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:07:28Z","timestamp":1789020448274,"version":"build-2803163510"},"reference-count":73,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS\u20102024\u201000397681"],"award-info":[{"award-number":["RS\u20102024\u201000397681"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS\u20102024\u201000440614"],"award-info":[{"award-number":["RS\u20102024\u201000440614"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS\u20102024\u201000440289"],"award-info":[{"award-number":["RS\u20102024\u201000440289"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS\u20102025\u201000523615"],"award-info":[{"award-number":["RS\u20102025\u201000523615"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS\u20102025\u201000523575"],"award-info":[{"award-number":["RS\u20102025\u201000523575"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS\u20102024\u201000443714"],"award-info":[{"award-number":["RS\u20102024\u201000443714"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010446","name":"Institute for Basic Science","doi-asserted-by":"publisher","award":["IBS\u2010R001\u2010Y4"],"award-info":[{"award-number":["IBS\u2010R001\u2010Y4"]}],"id":[{"id":"10.13039\/501100010446","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Vascular endothelial growth factor\u2010C (VEGF\u2010C) and its receptor VEGFR\u20103 are critical for lymphangiogenesis, yet the structural mechanisms beyond simple dimerization that drive activation remain unknown. Here, we report the first cryo\u2010EM structure of the human VEGFR\u20103 full ectodomain in complex with VEGF\u2010C. Such a canonical ligand\u2010induced 2:2 hetero\u2010tetrameric complex further self\u2010assembles into distinct higher\u2010order assemblies\u2014a lateral\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010cluster and an inverted\n                    <jats:italic>trans<\/jats:italic>\n                    \u2010like\u2010cluster. Further analysis of these canonical 2:2 hetero\u2010tetramer in higher\u2010order assemblies identifies that the specificity of VEGF\u2010C for VEGFR\u20103 and VEGFR\u20102 over VEGFR\u20101 is mainly governed by its N\u2010terminal \u03b11 helix, which is structurally accommodated by the D2 domains of VEGFR\u20103 and VEGFR\u20102 but sterically excluded by the protruding D1\u2013D2 connecting loop of VEGFR\u20101. Furthermore, we identify a unique interface within the membrane\u2010proximal D5 domain occurring between neighboring canonical 2:2 complexes, mediated by a specific \u201cWTP motif,\u201d as a key driver of\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010clustering. Structure\u2010guided mutagenesis and real\u2010time optogenetic assays support a critical role for\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010clustering in signal amplification and show that enforced receptor clustering can drive robust activation, whereas\n                    <jats:italic>trans<\/jats:italic>\n                    \u2010like\u2010clustering appears dispensable. Collectively, these findings transform the traditional \u201cmonomer\u2010to\u2010dimer\u201d activation model of VEGFR\u20103\/VEGF\u2010C into a \u201cdimer\u2010to\u2010cluster\u201d paradigm, providing a blueprint for engineering next\u2010generation therapeutics targeting lymphatic vascular diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.77728","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:54:36Z","timestamp":1789019676000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural Basis of Lymphangiogenic Receptor VEGFR\u20103 Activation Mediated by Distinctive Clustering of the Ligand\u2013Receptor Complex"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0005-4864","authenticated-orcid":false,"given":"Ryeongeun","family":"Cho","sequence":"first","affiliation":[{"name":"InnoCORE AI\u2010CRED Institute Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"},{"name":"Graduate School of Medical Science and Engineering Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4175-5181","authenticated-orcid":false,"given":"Jinsook","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0484-6639","authenticated-orcid":false,"given":"Jimin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology Jeonbuk National University  Jeonju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Sun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7531-2141","authenticated-orcid":false,"given":"Gahi","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology Jeonbuk National University  Jeonju Republic of Korea"},{"name":"Research Institute for Materials and Energy Sciences Jeonbuk National University  Jeonju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6916-3372","authenticated-orcid":false,"given":"Sangkyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Memory and Glioscience Institute for Basic Science (IBS)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0029-3643","authenticated-orcid":false,"given":"Ho Min","family":"Kim","sequence":"additional","affiliation":[{"name":"InnoCORE AI\u2010CRED Institute Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"},{"name":"Department of Biological Sciences Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2008.12.012"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.87"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2545"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.117585"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010025\u201002249\u20100"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02\u20100401fje"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.965384"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201023546\u20106"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009092"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology10020167"},{"issue":"18","key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"4919","DOI":"10.1002\/j.1460-2075.1996.tb00872.x","article-title":"The second immunoglobulin\u2010like domain of the VEGF tyrosine kinase receptor Flt\u20101 determines ligand binding and may initiate a signal transduction cascade","volume":"15","author":"Davis\u2010Smyth T.","year":"1996","journal-title":"The EMBO Journal"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.16.10382"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2016.12.012"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1301415110"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1911"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2014.89"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1004148107"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.02.031"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.14107"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1782"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.5.1988"},{"key":"e_1_2_9_23_1","first-page":"3545","article-title":"Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors","volume":"9","author":"Pajusola K.","year":"1994","journal-title":"Oncogene"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.11.001"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914318107"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.197830"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi401518b"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb1202"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.130658"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102011\u201011\u2010390922"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.13.3898"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039558"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.009"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.04.039"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1524"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2360"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010017\u201000060\u20102"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010017\u201000648\u20108"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5057"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5925"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102010\u201008\u2010301549"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511593200"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.12.6599"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.17.4762"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201026620\u20101"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108187"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M102315200"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.4204\/EPTCS.125.3"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200906044"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/35004044"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.01\u201008\u20100411"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.12.032"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1715"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1714"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/414933a"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2015.01.018"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2020.102017"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa054481"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2014.32.15_suppl.2524"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2023.02.001"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1158\/2767\u20109764.CRC\u201022\u20100151"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.002779"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2011.04.093"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4169"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4193"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010019\u20100580\u2010y"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2115"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2003.07.013"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2013.08.002"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010021\u201002399\u20101"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007487\u2010w"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904019158"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909052925"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3943"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.77728","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.77728","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.77728","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:54:38Z","timestamp":1789019678000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.77728"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":73,"alternative-id":["10.1002\/advs.77728"],"URL":"https:\/\/doi.org\/10.1002\/advs.77728","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"assertion":[{"value":"2026-01-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e77728"}}