{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T18:04:16Z","timestamp":1784916256577,"version":"3.55.0"},"reference-count":50,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"30","funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["S10OD032437"],"award-info":[{"award-number":["S10OD032437"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of General Medical Sciences, National Institutes of Health","award":["R35GM151043"],"award-info":[{"award-number":["R35GM151043"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,7,24]]},"abstract":"<jats:p>Glycoprotein B (gB) of herpesviruses mediates membrane fusion with host cells during viral entry. Stabilizing gB in its prefusion conformation is a primary strategy for vaccine development. While prefusion-like gB structures of several human herpesviruses have been solved, the native conformational landscape and structural dynamics of gB remain largely unknown. Here, we report cryo\u2013electron microscopy structures of herpes simplex virus type 1 (HSV-1) gB from virions, revealing a predominant prefusion state and a minor population of an intermediate, primed state. Unique to \u03b1-herpesviruses, a tethering helix cross-links adjacent protomers and stabilizes these conformations. A further downstream intermediate we named as the deep-primed state was captured in a mutant and showed that structural changes in the central helices drive the disengagement of the fusion loops from the membrane-proximal regions, priming gB for membrane insertion. Leveraging these structural insights, we engineered gB mutants locked in distinct conformational states. Our findings provide an atlas for designing gB-based vaccines more closely mimicking the infectious virus.<\/jats:p>","DOI":"10.1126\/sciadv.aed8023","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T17:58:33Z","timestamp":1784915913000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["The native conformational landscape and priming mechanism of herpes simplex virus glycoprotein B"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1908-617X","authenticated-orcid":true,"given":"Zongjun","family":"Mou","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8221-4339","authenticated-orcid":true,"given":"Shanshan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Swanback","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peicheng","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2663-5731","authenticated-orcid":true,"given":"Jordan","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2629-0136","authenticated-orcid":true,"given":"Bibekananda","family":"Sahoo","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4102-3175","authenticated-orcid":true,"given":"Xinghong","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","first-page":"212","article-title":"The family Herpesviridae: A brief introduction","volume":"2","author":"Krug L.","year":"2021","unstructured":"L. Krug, P. Pellett, The family Herpesviridae: A brief introduction. Fields Virol. DNA Virus. 2, 212\u2013234 (2021).","journal-title":"Fields Virol. DNA Virus."},{"key":"e_1_3_2_3_2","first-page":"297","article-title":"Herpes simplex viruses: Pathogenesis and clinical insights","volume":"2","author":"Whitley R.","year":"2021","unstructured":"R. Whitley, C. Johnston, Herpes simplex viruses: Pathogenesis and clinical insights. Fields Virol. DNA Virus. 2, 297\u2013323 (2021).","journal-title":"Fields Virol. DNA Virus."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.9.3.431-439.1972"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00904-08"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.1.873-875.1998"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00143-21"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-020-00448-w"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01700-10"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.62.4.1347-1354.1988"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56419-3"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/309633a0"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0040148"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.10.8257-8263.1998"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1126548"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-018-0060-6"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1243283"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2018.10.032"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1707304114"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-34171-7"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb2507"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abf3178"},{"key":"e_1_3_2_23_2","doi-asserted-by":"crossref","unstructured":"M. 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Veesler Computational design of prefusion-stabilized herpesvirus gB trimers. bioRxiv 2024.10.23.619923 [Preprint] (2024). https:\/\/doi.org\/10.1101\/2024.10.23.619923.","DOI":"10.1101\/2024.10.23.619923"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09438-5"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-025-02153-x"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-67969-x"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abc1726"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007452"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao7298"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-022-2139-2"},{"key":"e_1_3_2_31_2","doi-asserted-by":"crossref","first-page":"e0203922","DOI":"10.1128\/mbio.02039-22","article-title":"Herpes simplex virus 1 entry glycoproteins form complexes before and during membrane fusion","volume":"13","author":"Pataki Z.","year":"2022","unstructured":"Z. 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