{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:05:49Z","timestamp":1790287549956,"version":"4.1.0"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"29","license":[{"start":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T00:00:00Z","timestamp":1720569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["P01HL139420"],"award-info":[{"award-number":["P01HL139420"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P30GM124165"],"award-info":[{"award-number":["P30GM124165"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,7,16]]},"abstract":"<jats:p>\n                    Hemostasis relies on a reaction network of serine proteases and their cofactors to form a blood clot. Coagulation factor IXa (protease) plays an essential role in hemostasis as evident from the bleeding disease associated with its absence. RNA aptamers specifically targeting individual coagulation factors have potential as anticoagulants and as probes of the relationship between structure and function. Here, we report X-ray structures of human factor IXa without a ligand bound to the active site either in the apo-form or in complex with an inhibitory aptamer specific for factor IXa. The aptamer binds to an exosite in the catalytic domain and allosterically distorts the active site. Our studies reveal a conformational ensemble of IXa states, wherein large movements of Trp\n                    <jats:sub>215<\/jats:sub>\n                    near the active site drive functional transitions between the closed (aptamer-bound), latent (apo), and open (substrate-bound) states. The latent state of the apo-enzyme may bear on the uniquely poor catalytic activity of IXa compared to other coagulation proteases. The exosite, to which the aptamer binds, has been implicated in binding VIIIa and heparin, both of which regulate IXa function. Our findings reveal the importance of exosite-driven allosteric modulation of IXa function and new strategies to rebalance hemostasis for therapeutic gain.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2401136121","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T13:34:02Z","timestamp":1720618442000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":15,"title":["An RNA aptamer exploits exosite-dependent allostery to achieve specific inhibition of coagulation factor IXa"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4008-2461","authenticated-orcid":false,"given":"Vladimir N.","family":"Kolyadko","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana M.","family":"Layzer","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4046-1704","authenticated-orcid":false,"given":"Kay","family":"Perry","sequence":"additional","affiliation":[{"name":"Northeastern Collaborative Access Team, Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, IL 60439"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5113-5541","authenticated-orcid":false,"given":"Bruce A.","family":"Sullenger","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sriram","family":"Krishnaswamy","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104"},{"name":"Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,7,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0061-0"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.145.3638.1310"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/202498a0"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.57.070188.004411"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.17.10709"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(88)90567-3"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1657577"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V76.1.1.1"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R800035200"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.25.14379"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi047934a"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006961200"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.154914"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/2.3.293"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000405"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.20.12089"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0904377"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.216713"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(22)00113-2"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature00963"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.300772"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2021.12.011"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2007.02496.x"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.26.18477"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(93)22033-C"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910144107"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4153"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.049833"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-2126(99)80125-7"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.21.9796"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2009.10.011"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.698613"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(84)90465-X"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar50123a006"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M802205200"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.723072"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc2754"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.015325"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)47089-5"},{"key":"e_1_3_4_40_2","doi-asserted-by":"crossref","unstructured":"V.N Kolyadko S. Krishnaswamy Crystal structure of human coagulation factor IXa (S195A) apo-form DES-GLA. https:\/\/www.rcsb.org\/structure\/8EPH DOI: https:\/\/doi.org\/10.2210\/pdb8EPH\/pdb Deposited: 5 October 2022.","DOI":"10.2210\/pdb8eph\/pdb"},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","unstructured":"V.N Kolyadko S. Krishnaswamy Crystal structure of human coagulation factor IXa (S195A) apo-form. https:\/\/www.rcsb.org\/structure\/8EPC DOI: https:\/\/doi.org\/10.2210\/pdb8EPC\/pdb Deposited: 5 October 2022.","DOI":"10.2210\/pdb8epc\/pdb"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","unstructured":"V.N Kolyadko S. Krishnaswamy Complex of anticoagulant RNA aptamer and human coagulation factor IXa (S195A). https:\/\/www.rcsb.org\/structure\/8EPK DOI: https:\/\/doi.org\/10.2210\/pdb8EPK\/pdb Deposited: 5 October 2022.","DOI":"10.2210\/pdb8EPK\/pdb"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2401136121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T13:36:02Z","timestamp":1720618562000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2401136121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,10]]},"references-count":42,"journal-issue":{"issue":"29","published-print":{"date-parts":[[2024,7,16]]}},"alternative-id":["10.1073\/pnas.2401136121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2401136121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,10]]},"assertion":[{"value":"2024-01-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2401136121"}}