{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T23:41:24Z","timestamp":1767397284702,"version":"3.48.0"},"reference-count":56,"publisher":"Georg Thieme Verlag KG","issue":"01","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health\u223cHolland, Top Sector Life Sciences & Health","award":["LSHM19064"],"award-info":[{"award-number":["LSHM19064"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Direct anticoagulants inhibit coagulation serine proteases by reversibly engaging their active site with high affinity. By modifying the S4 active site subpocket of factor (F)Xa, we introduced inhibitor resistance while preserving catalytic activity. Given the homology between FXa and thrombin in active site architecture and direct anticoagulant binding, we have targeted the S4 subsite to introduce inhibitor resistance in (pro)thrombin.<\/jats:p>\n                  <jats:p>Recombinant prothrombin variants were generated in which I174 was substituted or sequence R92-N98 was exchanged with that of human kallikrein-3.<\/jats:p>\n                  <jats:p>Specific prothrombin clotting activity of the variants was 6-fold (intrinsic clotting) to 10-fold (extrinsic clotting) reduced relative to wild-type prothrombin. Further analyses revealed that modification of the S4 subsite hampers fibrinogen and thrombomodulin-mediated protein C conversion by thrombin. Consistent with this, the thrombin variants displayed a reduced catalytic efficiency toward the peptidyl substrate used in thrombin generation assessments. The variants displayed a 2-fold reduced sensitivity for dabigatran relative to wild-type prothrombin, while argatroban inhibition was unaffected. Analyses using a purified component system revealed an up to 24-fold and 4-fold reduced IC50 for inhibition of thrombin by dabigatran and argatroban, respectively. Molecular dynamics (MD) simulations of both dabigatran-bound and unbound (apo) modified thrombin variants indicated these to comprise a larger inhibitor binding pocket relative to wild-type thrombin and display reduced inhibitor binding. As a net effect, (pro)thrombin variants with S4 subsite modifications supported detectable fibrin formation at therapeutic dabigatran concentrations.<\/jats:p>\n                  <jats:p>Our findings provide proof-of-concept for the engineering of thrombin variants that are resistant to direct thrombin inhibitors by modulating the S4 subsite.<\/jats:p>","DOI":"10.1055\/a-2537-6037","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T19:21:01Z","timestamp":1739388061000},"page":"023-036","source":"Crossref","is-referenced-by-count":1,"title":["Modifications of the Prothrombin Active Site S4 Subpocket Confer Resistance to Dabigatran"],"prefix":"10.1055","volume":"126","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1530-0818","authenticated-orcid":false,"given":"Viola J.F.","family":"Strijbis","sequence":"first","affiliation":[{"name":"Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"VarmX B.V., Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ka Lei","family":"Cheung","sequence":"first","affiliation":[{"name":"Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1042-7211","authenticated-orcid":false,"given":"Dejvid","family":"Veizaj","sequence":"additional","affiliation":[{"name":"Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tessa","family":"Rutten","sequence":"additional","affiliation":[{"name":"Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boris","family":"de Bruin","sequence":"additional","affiliation":[{"name":"Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pieter H.","family":"Reitsma","sequence":"additional","affiliation":[{"name":"Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"VarmX B.V., Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1604-6965","authenticated-orcid":false,"given":"Dani\u00ebl","family":"Verhoef","sequence":"additional","affiliation":[{"name":"Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"VarmX B.V., Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8164-817X","authenticated-orcid":false,"given":"Mettine H.A.","family":"Bos","sequence":"additional","affiliation":[{"name":"Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"issue":"11","key":"ref1","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1002\/j.1460-2075.1989.tb08511.x","article-title":"The refined 1.9 A crystal structure of human alpha-thrombin: interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment","volume":"8","author":"W Bode","year":"1989","journal-title":"EMBO J"},{"issue":"12","key":"ref2","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1021\/cr000033x","article-title":"Serine protease mechanism and specificity","volume":"102","author":"L Hedstrom","year":"2002","journal-title":"Chem Rev"},{"issue":"12","key":"ref3","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1056\/NEJMoa0905561","article-title":"Dabigatran versus warfarin in patients with atrial fibrillation","volume":"361","author":"S J 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Fischer","year":"2018","journal-title":"J Med Chem"},{"issue":"05","key":"ref17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/ejh.12610","article-title":"Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives","volume":"95","author":"A G\u00f3mez-Outes","year":"2015","journal-title":"Eur J Haematol"},{"issue":"08","key":"ref18","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1055\/s-0040-1709134","article-title":"Reversal agents for the direct factor Xa inhibitors: biochemical mechanisms of current and newly emerging therapies","volume":"46","author":"M Schreuder","year":"2020","journal-title":"Semin Thromb Hemost"},{"issue":"20","key":"ref19","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1093\/eurheartj\/ehad123","article-title":"Reversal agents for current and forthcoming direct oral anticoagulants","volume":"44","author":"N van Es","year":"2023","journal-title":"Eur Heart 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Lechtenberg","year":"2013","journal-title":"Blood"},{"issue":"20","key":"ref29","doi-asserted-by":"crossref","first-page":"21643","DOI":"10.1074\/jbc.M402107200","article-title":"Removal of B-domain sequences from factor V rather than specific proteolysis underlies the mechanism by which cofactor function is realized","volume":"279","author":"R Toso","year":"2004","journal-title":"J Biol Chem"},{"issue":"01","key":"ref30","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1159\/000071636","article-title":"Calibrated automated thrombin generation measurement in clotting plasma","volume":"33","author":"H C Hemker","year":"2003","journal-title":"Pathophysiol Haemost Thromb"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12959-018-0164-6","article-title":"Thrombin generation in low plasma volumes","volume":"16","author":"S Bloemen","year":"2018","journal-title":"Thromb J"},{"issue":"16","key":"ref32","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber biomolecular simulation programs","volume":"26","author":"D A Case","year":"2005","journal-title":"J Comput Chem"},{"volume-title":"Amber 2022","year":"2022","author":"D A Case","key":"ref33"},{"issue":"06","key":"ref34","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41592-022-01488-1","article-title":"ColabFold: making protein folding accessible to all","volume":"19","author":"M Mirdita","year":"2022","journal-title":"Nat Methods"},{"issue":"7873","key":"ref35","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"J Jumper","year":"2021","journal-title":"Nature"},{"issue":"05","key":"ref36","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities","volume":"10","author":"S Genheden","year":"2015","journal-title":"Expert Opin Drug Discov"},{"issue":"09","key":"ref37","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/ct300418h","article-title":"MMPBSA.py: an efficient program for end-state free energy calculations","volume":"8","author":"B R Miller III","year":"2012","journal-title":"J Chem Theory Comput"},{"issue":"04","key":"ref38","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/0022-2836(92)91054-S","article-title":"Refined 2.3 A X-ray crystal structure of bovine thrombin complexes formed with the benzamidine and arginine-based thrombin inhibitors NAPAP, 4-TAPAP and MQPA. A starting point for improving antithrombotics","volume":"226","author":"H Brandstetter","year":"1992","journal-title":"J Mol Biol"},{"issue":"09","key":"ref39","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1021\/jm0109513","article-title":"Structure-based design of novel potent nonpeptide thrombin inhibitors","volume":"45","author":"N H Hauel","year":"2002","journal-title":"J Med Chem"},{"issue":"02","key":"ref40","first-page":"333","article-title":"Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats","volume":"98","author":"W Wienen","year":"2007","journal-title":"Thromb Haemost"},{"issue":"06","key":"ref41","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1097\/00019501-199606000-00008","article-title":"Argatroban: a synthetic thrombin inhibitor of low relative molecular mass","volume":"7","author":"D Fitzgerald","year":"1996","journal-title":"Coron Artery Dis"},{"issue":"02","key":"ref42","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3390\/pharmaceutics14020257","article-title":"Dabigatran acylglucuronide, the major metabolite of dabigatran, shows a weaker anticoagulant effect than dabigatran","volume":"14","author":"J M Kim","year":"2022","journal-title":"Pharmaceutics"},{"issue":"S 01","key":"ref43","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1055\/s-2006-939550","article-title":"An overview of the structure and function of thrombin","volume":"32","author":"E W Davie","year":"2006","journal-title":"Semin Thromb Hemost"},{"issue":"03","key":"ref44","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/prot.10627","article-title":"Characterization of a thrombomodulin binding site on protein C and its comparison to an activated protein C binding site for factor Va","volume":"54","author":"A J Gale","year":"2004","journal-title":"Proteins"},{"issue":"01","key":"ref45","doi-asserted-by":"crossref","first-page":"11079","DOI":"10.1038\/s41598-020-68078-z","article-title":"Role of the activation peptide in the mechanism of protein C activation","volume":"10","author":"B M Stojanovski","year":"2020","journal-title":"Sci Rep"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1111\/j.1749-6632.2001.tb03530.x","article-title":"Mutation of W215 compromises thrombin cleavage of fibrinogen, but not of PAR1 or protein C","volume":"936","author":"Y M Ayala","year":"2001","journal-title":"Ann N Y Acad Sci"},{"issue":"18","key":"ref47","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.1021\/acs.biochem.8b00262","article-title":"Dynamic consequences of mutation of tryptophan 215 in thrombin","volume":"57","author":"R B Peacock","year":"2018","journal-title":"Biochemistry"},{"issue":"18","key":"ref48","doi-asserted-by":"crossref","first-page":"e202203473","DOI":"10.1002\/chem.202203473","article-title":"Activity sensing of coagulation and fibrinolytic proteases","volume":"29","author":"D Sondag","year":"2023","journal-title":"Chemistry"},{"issue":"05","key":"ref49","doi-asserted-by":"crossref","first-page":"e63988","DOI":"10.1371\/journal.pone.0063988","article-title":"Population divergence in venom bioactivities of elapid snake Pseudonaja textilis: role of procoagulant proteins in rapid rodent prey incapacitation","volume":"8","author":"J Skeji\u0107","year":"2013","journal-title":"PLoS One"},{"issue":"06","key":"ref50","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1111\/j.1538-7836.2006.01969.x","article-title":"Molecular evolution caught in action: gene duplication and evolution of molecular isoforms of prothrombin activators in Pseudonaja textilis (brown snake)","volume":"4","author":"M A Reza","year":"2006","journal-title":"J Thromb Haemost"},{"issue":"S 01","key":"ref51","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1538-7836.2007.02496.x","article-title":"Exosites in the substrate specificity of blood coagulation reactions","volume":"5","author":"P E Bock","year":"2007","journal-title":"J Thromb Haemost"},{"issue":"02","key":"ref52","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.1432-1033.1981.tb05702.x","article-title":"Active site of alpha-lytic protease: enzyme-substrate interactions","volume":"120","author":"C A Bauer","year":"1981","journal-title":"Eur J Biochem"},{"issue":"01","key":"ref53","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/jth.12045","article-title":"Platelet-based coagulation: different populations, different functions","volume":"11","author":"J W Heemskerk","year":"2013","journal-title":"J Thromb 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