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The 2.8 A crystal structure of Gla-domainless activated protein C.

Mather T, Oganessyan V, Hof P, Huber R, Foundling S, Esmon C, Bode W
EMBO J 15 6822-31 (1996)
Cited: 121 times
EuropePMC logo PMID: 9003757

Abstract

The structure of the Gla-domainless form of the human anticoagulant enzyme activated protein C has been solved at 2.8 A resolution. The light chain is composed of two domains: an epidermal growth factor (EGF)-like domain modified by a large insert containing an additional disulfide, followed by a typical EGF-like domain. The arrangement of the long axis of these domains describes an angle of approximately 80 degrees. Disulfide linked to the light chain is the catalytic domain, which is generally trypsin-like but contains a large insertion loop at the edge of the active site, a third helical segment, a prominent cationic patch analogous to the anion binding exosite I of thrombin and a trypsin-like Ca[II] binding site. The arrangement of loops around the active site partially restricts access to the cleft. The S2 and S4 subsites are much more polar than in factor Xa and thrombin, and the S2 site is unrestricted. While quite open and exposed, the active site contains a prominent groove, the surface of which is very polar with evidence for binding sites on the primed side, in addition to those typical of the trypsin class found on the non-primed side.

Reviews - 1aut mentioned but not cited (6)

  1. Cytoprotective protein C pathways and implications for stroke and neurological disorders. Zlokovic BV, Griffin JH. Trends Neurosci 34 198-209 (2011)
  2. Exosites in the substrate specificity of blood coagulation reactions. Bock PE, Panizzi P, Verhamme IM. J Thromb Haemost 5 Suppl 1 81-94 (2007)
  3. Regulation of the protein C anticoagulant and antiinflammatory pathways. Rezaie AR. Curr Med Chem 17 2059-2069 (2010)
  4. Protein C anticoagulant and cytoprotective pathways. Griffin JH, Zlokovic BV, Mosnier LO. Int J Hematol 95 333-345 (2012)
  5. Activated protein C action in inflammation. Sarangi PP, Lee HW, Kim M. Br J Haematol 148 817-833 (2010)
  6. Cytoprotective-selective activated protein C therapy for ischaemic stroke. Mosnier LO, Zlokovic BV, Griffin JH. Thromb Haemost 112 883-892 (2014)

Articles - 1aut mentioned but not cited (22)

  1. Rational design of coagulation factor VIIa variants with substantially increased intrinsic activity. Persson E, Kjalke M, Olsen OH. Proc Natl Acad Sci U S A 98 13583-13588 (2001)
  2. Crystal structure of the catalytic domain of human complement c1s: a serine protease with a handle. Gaboriaud C, Rossi V, Bally I, Arlaud GJ, Fontecilla-Camps JC. EMBO J 19 1755-1765 (2000)
  3. Ligand recognition specificity of leukocyte integrin αMβ2 (Mac-1, CD11b/CD18) and its functional consequences. Podolnikova NP, Podolnikov AV, Haas TA, Lishko VK, Ugarova TP. Biochemistry 54 1408-1420 (2015)
  4. Engineering the proteolytic specificity of activated protein C improves its pharmacological properties. Berg DT, Gerlitz B, Shang J, Smith T, Santa P, Richardson MA, Kurz KD, Grinnell BW, Mace K, Jones BE. Proc Natl Acad Sci U S A 100 4423-4428 (2003)
  5. Demonstration of the extrinsic coagulation pathway in teleostei: identification of zebrafish coagulation factor VII. Sheehan J, Templer M, Gregory M, Hanumanthaiah R, Troyer D, Phan T, Thankavel B, Jagadeeswaran P. Proc Natl Acad Sci U S A 98 8768-8773 (2001)
  6. A thrombin-cross-reactive anticardiolipin antibody binds to and inhibits the anticoagulant function of activated protein C. Hwang KK, Yang CD, Yan W, Grossman JM, Hahn BH, Chen PP. Arthritis Rheum 48 1622-1630 (2003)
  7. Activation of protein C by the thrombin-thrombomodulin complex: cooperative roles of Arg-35 of thrombin and Arg-67 of protein C. Yang L, Manithody C, Rezaie AR. Proc Natl Acad Sci U S A 103 879-884 (2006)
  8. ProCMD: a database and 3D web resource for protein C mutants. D'Ursi P, Marino F, Caprera A, Milanesi L, Faioni EM, Rovida E. BMC Bioinformatics 8 Suppl 1 S11 (2007)
  9. Activated protein C N-linked glycans modulate cytoprotective signaling function on endothelial cells. Ní Ainle F, O'Donnell JS, Johnson JA, Brown L, Gleeson EM, Smith OP, Preston RJ. J Biol Chem 286 1323-1330 (2011)
  10. Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia. Zhao XY, Wilmen A, Wang D, Wang X, Bauzon M, Kim JY, Linden L, Li L, Egner U, Marquardt T, Moosmayer D, Tebbe J, Glück JM, Ellinger P, McLean K, Yuan S, Yegneswaran S, Jiang X, Evans V, Gu JM, Schneider D, Zhu Y, Xu Y, Mallari C, Hesslein A, Wang Y, Schmidt N, Gutberlet K, Ruehl-Fehlert C, Freyberger A, Hermiston T, Patel C, Sim D, Mosnier LO, Laux V. Nat Commun 11 2992 (2020)
  11. Inhibition of thrombin formation by active site mutated (S360A) activated protein C. Nicolaes GA, Bock PE, Segers K, Wildhagen KC, Dahlbäck B, Rosing J. J Biol Chem 285 22890-22900 (2010)
  12. Structural descriptor database: a new tool for sequence-based functional site prediction. Bernardes JS, Fernandez JH, Vasconcelos AT. BMC Bioinformatics 9 492 (2008)
  13. Activated Protein C Attenuates Severe Inflammation by Targeting VLA-3high Neutrophil Subpopulation in Mice. Sarangi PP, Lee HW, Lerman YV, Trzeciak A, Harrower EJ, Rezaie AR, Kim M. J Immunol 199 2930-2936 (2017)
  14. Epitope Fingerprinting for Recognition of the Polyclonal Serum Autoantibodies of Alzheimer's Disease. de Oliveira-Júnior LC, Araújo Santos Fde A, Goulart LR, Ueira-Vieira C. Biomed Res Int 2015 267989 (2015)
  15. Unreported intrinsic disorder in proteins: Building connections to the literature on IDPs. Uversky VN. Intrinsically Disord Proteins 2 e970499 (2014)
  16. Variable contributions of basic residues forming an APC exosite in the binding and inactivation of factor VIIIa. Takeyama M, Wintermute JM, Manithody C, Rezaie AR, Fay PJ. Biochemistry 52 2228-2235 (2013)
  17. C-terminal residues of activated protein C light chain contribute to its anticoagulant and cytoprotective activities. Yamashita A, Zhang Y, Sanner MF, Griffin JH, Mosnier LO. J Thromb Haemost 18 1027-1038 (2020)
  18. 3D proteochemometrics: using three-dimensional information of proteins and ligands to address aspects of the selectivity of serine proteases. Subramanian V, Ain QU, Henno H, Pietilä LO, Fuchs JE, Prusis P, Bender A, Wohlfahrt G. Medchemcomm 8 1037-1045 (2017)
  19. Gly197Arg mutation in protein C causes recurrent thrombosis in a heterozygous carrier. Lu Y, Giri H, Villoutreix BO, Ding Q, Wang X, Rezaie AR. J Thromb Haemost 18 1141-1153 (2020)
  20. Computational analysis of the functional and structural impact of the most deleterious missense mutations in the human Protein C. Farajzadeh-Dehkordi M, Mafakher L, Harifi A, Samiee-Rad F, Rahmani B. PLoS One 18 e0294417 (2023)
  21. Quality Assessment of Selected Protein Structures Derived from Homology Modeling and AlphaFold. Binbay FA, Rathod DC, George AAP, Imhof D. Pharmaceuticals (Basel) 16 1662 (2023)
  22. Role of Gly197 in the structure and function of protein C. Lu Y, Biswas I, Villoutreix BO, Rezaie AR. Biochim Biophys Acta Gen Subj 1865 129892 (2021)


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  1. Proteases involved in cartilage matrix degradation in osteoarthritis. Troeberg L, Nagase H. Biochim Biophys Acta 1824 133-145 (2012)
  2. Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Dahlbäck B, Villoutreix BO. Arterioscler Thromb Vasc Biol 25 1311-1320 (2005)
  3. Activated protein C. Griffin JH, Fernández JA, Gale AJ, Mosnier LO. J Thromb Haemost 5 Suppl 1 73-80 (2007)
  4. Proteases as therapeutics. Craik CS, Page MJ, Madison EL. Biochem J 435 1-16 (2011)
  5. Structural and energetic determinants of the S1-site specificity in serine proteases. Czapinska H, Otlewski J. Eur J Biochem 260 571-595 (1999)
  6. Structure and interaction modes of thrombin. Bode W. Blood Cells Mol Dis 36 122-130 (2006)
  7. Molecular recognition in the protein C anticoagulant pathway. Dahlbäck B, Villoutreix BO. J Thromb Haemost 1 1525-1534 (2003)
  8. Structure-Function Relationship of the Interaction between Tissue Factor and Factor VIIa. Gajsiewicz JM, Morrissey JH. Semin Thromb Hemost 41 682-690 (2015)
  9. The structure-function relationship of activated protein C. Lessons from natural and engineered mutations. Wildhagen KC, Lutgens E, Loubele ST, ten Cate H, Nicolaes GA. Thromb Haemost 106 1034-1045 (2011)
  10. Surface loops of trypsin-like serine proteases as determinants of function. Goettig P, Brandstetter H, Magdolen V. Biochimie 166 52-76 (2019)
  11. The structure of thrombin, a chameleon-like proteinase. Bode W. J Thromb Haemost 3 2379-2388 (2005)

Articles citing this publication (82)

  1. Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Fuentes-Prior P, Iwanaga Y, Huber R, Pagila R, Rumennik G, Seto M, Morser J, Light DR, Bode W. Nature 404 518-525 (2000)
  2. The crystal structure of the endothelial protein C receptor and a bound phospholipid. Oganesyan V, Oganesyan N, Terzyan S, Qu D, Dauter Z, Esmon NL, Esmon CT. J Biol Chem 277 24851-24854 (2002)
  3. Identification of functional endothelial protein C receptor in human plasma. Kurosawa S, Stearns-Kurosawa DJ, Hidari N, Esmon CT. J Clin Invest 100 411-418 (1997)
  4. Structure of human factor VIIa and its implications for the triggering of blood coagulation. Pike AC, Brzozowski AM, Roberts SM, Olsen OH, Persson E. Proc Natl Acad Sci U S A 96 8925-8930 (1999)
  5. Design and characterization of an APC-specific serpin for the treatment of hemophilia. Polderdijk SG, Adams TE, Ivanciu L, Camire RM, Baglin TP, Huntington JA. Blood 129 105-113 (2017)
  6. Structural basis for chemical inhibition of human blood coagulation factor Xa. Kamata K, Kawamoto H, Honma T, Iwama T, Kim SH. Proc Natl Acad Sci U S A 95 6630-6635 (1998)
  7. Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Elphick GF, Sarangi PP, Hyun YM, Hollenbaugh JA, Ayala A, Biffl WL, Chung HL, Rezaie AR, McGrath JL, Topham DJ, Reichner JS, Kim M. Blood 113 4078-4085 (2009)
  8. Lysine 156 promotes the anomalous proenzyme activity of tPA: X-ray crystal structure of single-chain human tPA. Renatus M, Engh RA, Stubbs MT, Huber R, Fischer S, Kohnert U, Bode W. EMBO J 16 4797-4805 (1997)
  9. A monoclonal antibody against activated protein C allows rapid detection of activated protein C in plasma and reveals a calcium ion dependent epitope involved in factor Va inactivation. Liaw PC, Ferrell G, Esmon CT. J Thromb Haemost 1 662-670 (2003)
  10. Structure of extracellular tissue factor complexed with factor VIIa inhibited with a BPTI mutant. Zhang E, St Charles R, Tulinsky A. J Mol Biol 285 2089-2104 (1999)
  11. Hyperantithrombotic, noncytoprotective Glu149Ala-activated protein C mutant. Mosnier LO, Zampolli A, Kerschen EJ, Schuepbach RA, Banerjee Y, Fernández JA, Yang XV, Riewald M, Weiler H, Ruggeri ZM, Griffin JH. Blood 113 5970-5978 (2009)
  12. The structure of MBL-associated serine protease-2 reveals that identical substrate specificities of C1s and MASP-2 are realized through different sets of enzyme-substrate interactions. Harmat V, Gál P, Kardos J, Szilágyi K, Ambrus G, Végh B, Náray-Szabó G, Závodszky P. J Mol Biol 342 1533-1546 (2004)
  13. Converting blood coagulation factor IXa into factor Xa: dramatic increase in amidolytic activity identifies important active site determinants. Hopfner KP, Brandstetter H, Karcher A, Kopetzki E, Huber R, Engh RA, Bode W. EMBO J 16 6626-6635 (1997)
  14. Structural investigation of the A domains of human blood coagulation factor V by molecular modeling. Villoutreix BO, Dahlbäck B. Protein Sci 7 1317-1325 (1998)
  15. Some antiphospholipid antibodies recognize conformational epitopes shared by beta2-glycoprotein I and the homologous catalytic domains of several serine proteases. Lin WS, Chen PC, Yang CD, Cho E, Hahn BH, Grossman J, Hwang KK, Chen PP. Arthritis Rheum 56 1638-1647 (2007)
  16. A survey of left-handed helices in protein structures. Novotny M, Kleywegt GJ. J Mol Biol 347 231-241 (2005)
  17. Thrombomodulin allosterically modulates the activity of the anticoagulant thrombin. Rezaie AR, Yang L. Proc Natl Acad Sci U S A 100 12051-12056 (2003)
  18. Na+ site in blood coagulation factor IXa: effect on catalysis and factor VIIIa binding. Schmidt AE, Stewart JE, Mathur A, Krishnaswamy S, Bajaj SP. J Mol Biol 350 78-91 (2005)
  19. Identification of polyclonal and monoclonal antibodies against tissue plasminogen activator in the antiphospholipid syndrome. Lu CS, Horizon AA, Hwang KK, FitzGerald J, Lin WS, Hahn BH, Wallace DJ, Metzger AL, Weisman MH, Chen PP. Arthritis Rheum 52 4018-4027 (2005)
  20. Physiological fIXa activation involves a cooperative conformational rearrangement of the 99-loop. Sichler K, Kopetzki E, Huber R, Bode W, Hopfner KP, Brandstetter H. J Biol Chem 278 4121-4126 (2003)
  21. Assessing the relative importance of the biophysical properties of amino acid substitutions associated with human genetic disease. Terp BN, Cooper DN, Christensen IT, Jørgensen FS, Bross P, Gregersen N, Krawczak M. Hum Mutat 20 98-109 (2002)
  22. Inhibition of six serine proteinases of the human coagulation system by mutants of bovine pancreatic trypsin inhibitor. Grzesiak A, Krokoszynska I, Krowarsch D, Buczek O, Dadlez M, Otlewski J. J Biol Chem 275 33346-33352 (2000)
  23. Pore size--a key property for selective toxin removal in blood purification. Harm S, Falkenhagen D, Hartmann J. Int J Artif Organs 37 668-678 (2014)
  24. The conformation of the activation peptide of protein C is influenced by Ca2+ and Na+ binding. Yang L, Prasad S, Di Cera E, Rezaie AR. J Biol Chem 279 38519-38524 (2004)
  25. Capturing spontaneous partitioning of peripheral proteins using a biphasic membrane-mimetic model. Arcario MJ, Ohkubo YZ, Tajkhorshid E. J Phys Chem B 115 7029-7037 (2011)
  26. Modeling zymogen protein C. Perera L, Foley C, Darden TA, Stafford D, Mather T, Esmon CT, Pedersen LG. Biophys J 79 2925-2943 (2000)
  27. New enzyme lineages by subdomain shuffling. Hopfner KP, Kopetzki E, Kresse GB, Bode W, Huber R, Engh RA. Proc Natl Acad Sci U S A 95 9813-9818 (1998)
  28. Zymogenic and enzymatic properties of the 70-80 loop mutants of factor X/Xa. Chen L, Manithody C, Yang L, Rezaie AR. Protein Sci 13 431-442 (2004)
  29. A Double-Chambered Protein Nanocage Loaded with Thrombin Receptor Agonist Peptide (TRAP) and γ-Carboxyglutamic Acid of Protein C (PC-Gla) for Sepsis Treatment. Lee W, Seo J, Kwak S, Park EJ, Na DH, Kim S, Lee YM, Kim IS, Bae JS. Adv Mater 27 6637-6643 (2015)
  30. Probing the activation of protein C by the thrombin-thrombomodulin complex using structural analysis, site-directed mutagenesis, and computer modeling. Knobe KE, Berntsdotter A, Shen L, Morser J, Dahlbäck B, Villoutreix BO. Proteins 35 218-234 (1999)
  31. Activated protein C binds directly to Tie2: possible beneficial effects on endothelial barrier function. Minhas N, Xue M, Jackson CJ. Cell Mol Life Sci 74 1895-1906 (2017)
  32. Antibodies against the activated coagulation factor X (FXa) in the antiphospholipid syndrome that interfere with the FXa inactivation by antithrombin. Yang YH, Hwang KK, FitzGerald J, Grossman JM, Taylor M, Hahn BH, Chen PP. J Immunol 177 8219-8225 (2006)
  33. Conformational changes in activated protein C caused by binding of the first epidermal growth factor-like module of protein S. Hackeng TM, Yegneswaran S, Johnson AE, Griffin JH. Biochem J 349 Pt 3 757-764 (2000)
  34. Prothrombin residues 473-487 contribute to factor Va binding in the prothrombinase complex. Yegneswaran S, Mesters RM, Fernández JA, Griffin JH. J Biol Chem 279 49019-49025 (2004)
  35. Expression and functional characterisation of natural R147W and K150del variants of protein C in the Chinese population. Ding Q, Yang L, Hassanian SM, Rezaie AR. Thromb Haemost 109 614-624 (2013)
  36. Type II protein C deficiency: identification and molecular modelling of two natural mutants with low anticoagulant and normal amidolytic activity. Faioni EM, Hermida J, Rovida E, Razzari C, Asti D, Zeinali S, Mannucci PM. Br J Haematol 108 265-271 (2000)
  37. The RNA aptamer-binding site of hepatitis C virus NS3 protease. Hwang J, Fauzi H, Fukuda K, Sekiya S, Kakiuchi N, Shimotohno K, Taira K, Kusakabe I, Nishikawa S. Biochem Biophys Res Commun 279 557-562 (2000)
  38. The affinity of protein C for the thrombin.thrombomodulin complex is determined in a primary way by active site-dependent interactions. Lu G, Chhum S, Krishnaswamy S. J Biol Chem 280 15471-15478 (2005)
  39. Activated protein C: a potential cardioprotective factor against ischemic injury during ischemia/reperfusion. Wang J, Li J. Am J Transl Res 1 381-392 (2009)
  40. Drotrecogin alfa (activated). Lyseng-Williamson KA, Perry CM. Drugs 62 617-30; discussion 631-2 (2002)
  41. Evolutionary conserved rigid module-domain interactions can be detected at the sequence level: the examples of complement and blood coagulation proteases. Gaboriaud C, Rossi V, Fontecilla-Camps JC, Arlaud GJ. J Mol Biol 282 459-470 (1998)
  42. Protein C inhibitor directly and potently inhibits activated hepatocyte growth factor activator. Hayashi T, Nishioka J, Nakagawa N, Kamada H, Gabazza EC, Kobayashi T, Hattori A, Suzuki K. J Thromb Haemost 5 1477-1485 (2007)
  43. Residues surrounding Arg336 and Arg562 contribute to the disparate rates of proteolysis of factor VIIIa catalyzed by activated protein C. Varfaj F, Wakabayashi H, Fay PJ. J Biol Chem 282 20264-20272 (2007)
  44. Activation-dependent adsorption of cytokines and toxins related to liver failure to carbon beads. Tripisciano C, Kozynchenko OP, Linsberger I, Phillips GJ, Howell CA, Sandeman SR, Tennison SR, Mikhalovsky SV, Weber V, Falkenhagen D. Biomacromolecules 12 3733-3740 (2011)
  45. Characterization of a thrombomodulin binding site on protein C and its comparison to an activated protein C binding site for factor Va. Gale AJ, Griffin JH. Proteins 54 433-441 (2004)
  46. CoagMDB: a database analysis of missense mutations within four conserved domains in five vitamin K-dependent coagulation serine proteases using a text-mining tool. Saunders RE, Perkins SJ. Hum Mutat 29 333-344 (2008)
  47. Identification and computationally-based structural interpretation of naturally occurring variants of human protein C. Rovida E, Merati G, Merati G, D'Ursi P, Zanardelli S, Marino F, Fontana G, Castaman G, Faioni EM. Hum Mutat 28 345-355 (2007)
  48. The functional significance of the autolysis loop in protein C and activated protein C. Yang L, Manithody C, Rezaie AR. Thromb Haemost 94 60-68 (2005)
  49. Autolysis loop restricts the specificity of activated protein C: analysis by FRET and functional assays. Qureshi SH, Manithody C, Bae JS, Yang L, Rezaie AR. Biophys Chem 134 239-245 (2008)
  50. Chemical synthesis of human protein S thrombin-sensitive module and first epidermal growth factor module. Hackeng TM, Dawson PE, Kent SB, Griffin JH. Biopolymers 46 53-63 (1998)
  51. The protein C omega-loop substitution Asn2Ile is associated with reduced protein C anticoagulant activity. Preston RJ, Morse C, Murden SL, Brady SK, O'Donnell JS, Mumford AD. Br J Haematol 144 946-953 (2009)
  52. Letter A proposed structural model of human protein Z. Lee CJ, Chandrasekaran V, Duke RE, Perera L, Pedersen LG. J Thromb Haemost 5 1558-1561 (2007)
  53. Crystal structure of human factor VIIa/tissue factor in complex with peptide mimetic inhibitor. Kadono S, Sakamoto A, Kikuchi Y, Oh-eda M, Yabuta N, Koga T, Hattori K, Shiraishi T, Haramura M, Kodama H, Esaki T, Sato H, Watanabe Y, Itoh S, Ohta M, Kozono T. Biochem Biophys Res Commun 324 1227-1233 (2004)
  54. Function of the activated protein C (APC) autolysis loop in activated FVIII inactivation. Cramer TJ, Gale AJ. Br J Haematol 153 644-654 (2011)
  55. Mutagenesis studies toward understanding allostery in thrombin. Qureshi SH, Yang L, Manithody C, Iakhiaev AV, Rezaie AR. Biochemistry 48 8261-8270 (2009)
  56. Identification of novel small molecule inhibitors of activated protein C. Sperandio O, Wildhagen KC, Schrijver R, Wielders S, Villoutreix BO, Nicolaes GA. Thromb Res 133 1105-1114 (2014)
  57. Zymogen and activated protein C have similar structural architecture. Stojanovski BM, Pelc LA, Zuo X, Di Cera E. J Biol Chem 295 15236-15244 (2020)
  58. Altered inactivation pathway of factor Va by activated protein C in the presence of heparin. Nicolaes GA, Sørensen KW, Friedrich U, Tans G, Rosing J, Autin L, Dahlbäck B, Villoutreix BO. Eur J Biochem 271 2724-2736 (2004)
  59. Gly74Ser mutation in protein C causes thrombosis due to a defect in protein S-dependent anticoagulant function. Chen C, Yang L, Villoutreix BO, Wang X, Ding Q, Rezaie AR. Thromb Haemost 117 1358-1369 (2017)
  60. Screening the molecular surface of human anticoagulant protein C: a search for interaction sites. Villoutreix BO, Covell DG, Blom AM, Wallqvist A, Friedrich U, Dahlbäck B. J Comput Aided Mol Des 15 13-27 (2001)
  61. Down-regulation of the clotting cascade by the protein C pathway. Stavenuiter F, Bouwens EA, Mosnier LO. Hematol Educ 7 365-374 (2013)
  62. Growing insights into the potential benefits and risks of activated protein C administration in sepsis: a review of preclinical and clinical studies. Altaweel L, Sweeney D, Cui X, Barochia A, Natanson C, Eichacker PQ. Biologics 3 391-406 (2009)
  63. Ile73Asn mutation in protein C introduces a new N-linked glycosylation site on the first EGF-domain of protein C and causes thrombosis. Lu Y, Mehta-D'souza P, Biswas I, Villoutreix BO, Wang X, Ding Q, Rezaie AR. Haematologica 105 1712-1722 (2020)
  64. Parallel imaging of coagulation pathway proteases activated protein C, thrombin, and factor Xa in human plasma. Modrzycka S, Kołt S, Polderdijk SGI, Adams TE, Potoczek S, Huntington JA, Kasperkiewicz P, Drąg M. Chem Sci 13 6813-6829 (2022)
  65. Computational study of the putative active form of protein Z (PZa): sequence design and structural modeling. Chandrasekaran V, Lee CJ, Duke RE, Perera L, Pedersen LG. Protein Sci 17 1354-1361 (2008)
  66. Contribution of factor VIII light-chain residues 2007-2016 to an activated protein C-interactive site. Takeyama M, Wakabayashi H, Fay PJ. Thromb Haemost 109 187-198 (2013)
  67. Design, synthesis, and SAR of a series of activated protein C (APC) inhibitors with selectivity against thrombin for the treatment of haemophilia. Bach P, Knerr L, Fjellström O, Hansson K, Mattsson C, Gustafsson D. Bioorg Med Chem Lett 24 821-827 (2014)
  68. Role of the activation peptide in the mechanism of protein C activation. Stojanovski BM, Pelc LA, Di Cera E. Sci Rep 10 11079 (2020)
  69. The active site region plays a critical role in Na+ binding to thrombin. Pelc LA, Koester SK, Kukla CR, Chen Z, Di Cera E. J Biol Chem 298 101458 (2022)
  70. The role of P4-P3' residues flanking Arg336 in facilitating activated protein C-catalyzed cleavage and inactivation of factor VIIIa. DeAngelis JP, Varfaj F, Wakabayashi H, Fay PJ. Thromb Res 128 470-476 (2011)
  71. The role of autolysis loop in determining the specificity of coagulation proteases. Yang L, Manithody C, Rezaie AR. Braz J Med Biol Res 40 1055-1064 (2007)
  72. The roles of factor Va and protein S in formation of the activated protein C/protein S/factor Va inactivation complex. Gierula M, Salles-Crawley II, Santamaria S, Teraz-Orosz A, Crawley JTB, Crawley JTB, Lane DA, Ahnström J. J Thromb Haemost 17 2056-2068 (2019)
  73. Comparative sequence analysis of vitamin K-dependent coagulation factors. Stojanovski BM, Di Cera E. J Thromb Haemost 20 2837-2849 (2022)
  74. Know your APC. Di Cera E. Blood 113 5699-5700 (2009)
  75. Plasmin immunization preferentially induces potentially prothrombotic IgG anticardiolipin antibodies in MRL/MpJ mice. Ede K, Hwang KK, Wu CC, Wu M, Yang YH, Lin WS, Chien D, Chen PC, Tsao BP, McCurdy DK, Chen PP. Arthritis Rheum 60 3108-3117 (2009)
  76. A monoclonal antibody recognizing the activation domain of protein C in its calcium-free conformation. Vincenot A, Pittet JL, Aiach M, Gaussem P. FEBS Lett 432 94-97 (1998)
  77. Cleavage-Responsive Biofactory T Cells Suppress Infectious Diseases-Associated Hypercytokinemia. Kim H, Son B, Seo EU, Kwon M, Ahn JH, Shin H, Song GY, Park EJ, Na DH, Cho SW, Kim HN, Park HH, Lee W. Adv Sci (Weinh) 9 e2201883 (2022)
  78. Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma. Modrzycka S, Kołt S, Adams TE, Potoczek S, Huntington JA, Kasperkiewicz P, Drąg M. J Med Chem 66 3785-3797 (2023)
  79. Role of the gamma-carboxyglutamic acid domain of activated factor X in the presence of calcium during inhibition by antithrombin-heparin. Whinna HC, Lesesky EB, Monroe DM, High KA, Larson PJ, Church FC. J Thromb Haemost 2 1127-1134 (2004)
  80. Evaluation of prothrombotic risk of two PROC hotspot mutations (Arg189Trp and Lys193del) in Chinese population: a retrospective study. Li L, Li J, Wu X, Wu W, Ding Q, Qian B, Wang X. Thromb J 21 103 (2023)
  81. Identification of protein C epitopes altered during its nanoencapsulation. Chognot D, Zambaux MF, Bonneaux F, Gaussem P, Pittet JL, Aiach M, Vigneron C. J Protein Chem 18 779-784 (1999)
  82. Protective effects of activated protein C (APC) on free groin flaps after secondary venous stasis in the rat model. Wallmichrath J, Knab R, Baumeister RG, Holzbach T, Giunta RE, Frick A. Clin Hemorheol Microcirc 59 335-343 (2015)


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