2hgt › Citations

Structure of the hirugen and hirulog 1 complexes of alpha-thrombin.

Skrzypczak-Jankun E, Carperos VE, Ravichandran KG, Tulinsky A, Westbrook M, Maraganore JM
J Mol Biol 221 1379-93 (1991)
Cited: 133 times
EuropePMC logo PMID: 1942057

Abstract

The isomorphous structures of the hirugen (N-acetylhirudin 53'-64' with sulfato-Tyr63') and hirulog 1 (D-Phe-Pro-Arg-Pro-(Gly)4 desulfato-Tyr63'-hirugen) complexes of human alpha-thrombin have been determined and refined at 2.2 A resolution to crystallographic R-factors of 0.167 and 0.163, respectively. The binding of hirugen to thrombin is similar to that of the binding of the C-terminal dodecapeptide of hirudin, including that of the terminal 3(10) helical turn. The sulfato Tyr63', which, as a result of sulfation, increases the binding affinity by an order of magnitude, is involved in an extended hydrogen bonding network utilizing all three sulfato oxygen atoms. The hirugen-thrombin complex is the first thrombin structure determined to have an unobstructed active site; this site is practically identical in positioning of catalytic residues and in its hydrogen bonding pattern with that of other serine proteinases. Hirulog 1, which is a poor thrombin substrate, is cleaved at the Arg3'-Pro4' bond in the crystal structure. The Arg3' of hirulog 1 occupies the specificity site, the D-Phe-Pro-Arg tripeptide is positioned like that of D-Phe-Pro-Arg chloromethylketone in the active site and the Pro4'(Gly)4 spacer to hirugen is disordered in the structure, as is the 3(10) turn of hirugen. The latter must be related to the simultaneous absence both of sulfation and of the last residue of hirudin (Gln65'). In addition, the autolysis loop of thrombin (Lys145-Gly150) is disordered in both structures. Changes in circular dichroism upon hirugen binding are therefore most likely the result of the flexibility associated with this loop.

Articles - 2hgt mentioned but not cited (1)

  1. Crystal structure of thrombin in complex with S-variegin: insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors. Koh CY, Kumar S, Kazimirova M, Nuttall PA, Radhakrishnan UP, Kim S, Jagadeeswaran P, Imamura T, Mizuguchi J, Iwanaga S, Swaminathan K, Kini RM. PLoS ONE 6 e26367 (2011)


Reviews citing this publication (31)

  1. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Garcia DA, Baglin TP, Weitz JI, Samama MM. Chest 141 e24S-e43S (2012)
  2. A player of many parts: the spotlight falls on thrombin's structure. Stubbs MT, Bode W. Thromb. Res. 69 1-58 (1993)
  3. Cellular consequences of thrombin-receptor activation. Grand RJ, Turnell AS, Grabham PW. Biochem. J. 313 ( Pt 2) 353-368 (1996)
  4. The biology and enzymology of protein tyrosine O-sulfation. Moore KL. J. Biol. Chem. 278 24243-24246 (2003)
  5. Direct thrombin inhibitors in cardiovascular medicine. Lefkovits J, Topol EJ. Circulation 90 1522-1536 (1994)
  6. Exosites in the substrate specificity of blood coagulation reactions. Bock PE, Panizzi P, Verhamme IM. J. Thromb. Haemost. 5 Suppl 1 81-94 (2007)
  7. Direct thrombin inhibitors. Weitz JI, Crowther M. Thromb. Res. 106 V275-84 (2002)
  8. New anticoagulant drugs: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Weitz JI, Hirsh J, Samama MM. Chest 126 265S-286S (2004)
  9. Direct thrombin inhibitors for treatment of arterial thrombosis: potential differences between bivalirudin and hirudin. Bates SM, Weitz JI. Am. J. Cardiol. 82 12P-18P (1998)
  10. Novel antithrombotic drugs in development. Verstraete M, Zoldhelyi P. Drugs 49 856-884 (1995)
  11. Protein tyrosine sulfation, 1993--an update. Niehrs C, Beisswanger R, Huttner WB. Chem. Biol. Interact. 92 257-271 (1994)
  12. Toward a framework for sulfoproteomics: Synthesis and characterization of sulfotyrosine-containing peptides. Seibert C, Sakmar TP. Biopolymers 90 459-477 (2008)
  13. Structure and interaction modes of thrombin. Bode W. Blood Cells Mol. Dis. 36 122-130 (2006)
  14. Rate constants and mechanisms of intrinsically disordered proteins binding to structured targets. Zhou HX, Pang X, Lu C. Phys Chem Chem Phys 14 10466-10476 (2012)
  15. Translational success stories: development of direct thrombin inhibitors. Coppens M, Eikelboom JW, Gustafsson D, Weitz JI, Hirsh J. Circ. Res. 111 920-929 (2012)
  16. Small bite, large impact-saliva and salivary molecules in the medicinal leech, Hirudo medicinalis. Hildebrandt JP, Lemke S. Naturwissenschaften 98 995-1008 (2011)
  17. Proteinase inhibitors from the European medicinal leech Hirudo medicinalis: structural, functional and biomedical aspects. Ascenzi P, Amiconi G, Bode W, Bolognesi M, Coletta M, Menegatti E. Mol. Aspects Med. 16 215-313 (1995)
  18. Characterization of aptamer-protein complexes by X-ray crystallography and alternative approaches. Ruigrok VJ, Levisson M, Hekelaar J, Smidt H, Dijkstra BW, van der Oost J. Int J Mol Sci 13 10537-10552 (2012)
  19. Metalloproteases Affecting Blood Coagulation, Fibrinolysis and Platelet Aggregation from Snake Venoms: Definition and Nomenclature of Interaction Sites. Kini RM, Koh CY. Toxins (Basel) 8 (2016)
  20. The structure of thrombin, a chameleon-like proteinase. Bode W. J. Thromb. Haemost. 3 2379-2388 (2005)
  21. Emerging anticoagulant drugs. Bates SM, Weitz JI. Arterioscler. Thromb. Vasc. Biol. 23 1491-1500 (2003)
  22. Modes and consequences of thrombin's interaction with fibrin. Fredenburgh JC, Stafford AR, Pospisil CH, Weitz JI. Biophys. Chem. 112 277-284 (2004)
  23. Glyceraldehyde-3-phosphate dehydrogenase: Aggregation mechanisms and impact on amyloid neurodegenerative diseases. Muronetz VI, Barinova KV, Stroylova YY, Semenyuk PI, Schmalhausen EV. Int. J. Biol. Macromol. 100 55-66 (2017)
  24. Specific thrombin inhibitors in vivo. Fitzgerald D. Ann. N. Y. Acad. Sci. 714 41-52 (1994)
  25. Developments in antithrombotic therapy: state of the art anno 1996. ten Cate H, Nurmohamed MT, ten Cate JW. Pharm World Sci 18 195-203 (1996)
  26. Role of tyrosine-sulfated proteins in retinal structure and function. Kanan Y, Al-Ubaidi MR. Exp. Eye Res. 133 126-131 (2015)
  27. Exosite Binding in Thrombin: A Global Structural/Dynamic Overview of Complexes with Aptamers and Other Ligands. Troisi R, Balasco N, Autiero I, Vitagliano L, Sica F. Int J Mol Sci 22 10803 (2021)
  28. Proton Bridging in Catalysis by and Inhibition of Serine Proteases of the Blood Cascade System. Kovach IM. Life (Basel) 11 396 (2021)
  29. Bacterial staphylokinase as a promising third-generation drug in the treatment for vascular occlusion. Nedaeinia R, Faraji H, Javanmard SH, Ferns GA, Ghayour-Mobarhan M, Goli M, Mashkani B, Nedaeinia M, Haghighi MHH, Ranjbar M. Mol. Biol. Rep. 47 819-841 (2020)
  30. Diversity, Biosynthesis and Bioactivity of Aeruginosins, a Family of Cyanobacteria-Derived Nonribosomal Linear Tetrapeptides. Liu J, Zhang M, Huang Z, Fang J, Wang Z, Zhou C, Qiu X. Mar Drugs 21 217 (2023)
  31. Thrombolytic Enzymes of Microbial Origin: A Review. Diwan D, Usmani Z, Sharma M, Nelson JW, Thakur VK, Christie G, Molina G, Gupta VK. Int J Mol Sci 22 10468 (2021)

Articles citing this publication (101)

  1. Protease-activated receptor 3 is a second thrombin receptor in humans. Ishihara H, Connolly AJ, Zeng D, Kahn ML, Zheng YW, Timmons C, Tram T, Coughlin SR. Nature 386 502-506 (1997)
  2. Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLe(X) and PSGL-1. Somers WS, Tang J, Shaw GD, Camphausen RT. Cell 103 467-479 (2000)
  3. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI. Chest 133 141S-159S (2008)
  4. Refined structure of the hirudin-thrombin complex. Rydel TJ, Tulinsky A, Bode W, Huber R. J. Mol. Biol. 221 583-601 (1991)
  5. Thrombin functions as an inflammatory mediator through activation of its receptor. Cirino G, Cicala C, Bucci MR, Sorrentino L, Maraganore JM, Stone SR. J. Exp. Med. 183 821-827 (1996)
  6. Peptide exosite inhibitors of factor VIIa as anticoagulants. Dennis MS, Eigenbrot C, Skelton NJ, Ultsch MH, Santell L, Dwyer MA, O'Connell MP, Lazarus RA. Nature 404 465-470 (2000)
  7. Tyrosylprotein sulfotransferase: purification and molecular cloning of an enzyme that catalyzes tyrosine O-sulfation, a common posttranslational modification of eukaryotic proteins. Ouyang Yb, Lane WS, Moore KL. Proc. Natl. Acad. Sci. U.S.A. 95 2896-2901 (1998)
  8. 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. Brandstetter H, Turk D, Hoeffken HW, Grosse D, Stürzebecher J, Martin PD, Edwards BF, Bode W. J. Mol. Biol. 226 1085-1099 (1992)
  9. The isomorphous structures of prethrombin2, hirugen-, and PPACK-thrombin: changes accompanying activation and exosite binding to thrombin. Vijayalakshmi J, Padmanabhan KP, Mann KG, Tulinsky A. Protein Sci. 3 2254-2271 (1994)
  10. Transglutaminase factor XIII uses proteinase-like catalytic triad to crosslink macromolecules. Pedersen LC, Yee VC, Bishop PD, Le Trong I, Teller DC, Stenkamp RE. Protein Sci. 3 1131-1135 (1994)
  11. Recognition of a CXCR4 sulfotyrosine by the chemokine stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12). Veldkamp CT, Seibert C, Peterson FC, Sakmar TP, Volkman BF. J. Mol. Biol. 359 1400-1409 (2006)
  12. Pro- and anti-inflammatory actions of thrombin: a distinct role for proteinase-activated receptor-1 (PAR1). Vergnolle N, Hollenberg MD, Wallace JL. Br. J. Pharmacol. 126 1262-1268 (1999)
  13. Factorising ligand affinity: a combined thermodynamic and crystallographic study of trypsin and thrombin inhibition. Dullweber F, Stubbs MT, Musil D, Stürzebecher J, Klebe G. J. Mol. Biol. 313 593-614 (2001)
  14. Enzyme flexibility, solvent and 'weak' interactions characterize thrombin-ligand interactions: implications for drug design. Engh RA, Brandstetter H, Sucher G, Eichinger A, Baumann U, Bode W, Huber R, Poll T, Rudolph R, von der Saal W. Structure 4 1353-1362 (1996)
  15. Anticoagulant effects of hirulog, a novel thrombin inhibitor, in patients with coronary artery disease. Cannon CP, Maraganore JM, Loscalzo J, McAllister A, Eddings K, George D, Selwyn AP, Adelman B, Fox I, Braunwald E. Am. J. Cardiol. 71 778-782 (1993)
  16. The molecular basis of thrombin allostery revealed by a 1.8 A structure of the "slow" form. Huntington JA, Esmon CT. Structure 11 469-479 (2003)
  17. Variegin, a novel fast and tight binding thrombin inhibitor from the tropical bont tick. Koh CY, Kazimirova M, Trimnell A, Takac P, Labuda M, Nuttall PA, Kini RM. J Biol Chem 282 29101-29113 (2007)
  18. Electrostatic interactions in the association of proteins: an analysis of the thrombin-hirudin complex. Karshikov A, Bode W, Tulinsky A, Stone SR. Protein Sci. 1 727-735 (1992)
  19. Dominant role of local dipoles in stabilizing uncompensated charges on a sulfate sequestered in a periplasmic active transport protein. He JJ, Quiocho FA. Protein Sci. 2 1643-1647 (1993)
  20. Crystal structure of wild-type human thrombin in the Na+-free state. Johnson DJ, Adams TE, Li W, Huntington JA. Biochem. J. 392 21-28 (2005)
  21. Antithrombotic effects of synthetic peptides targeting various functional domains of thrombin. Kelly AB, Maraganore JM, Bourdon P, Hanson SR, Harker LA. Proc. Natl. Acad. Sci. U.S.A. 89 6040-6044 (1992)
  22. Cleavage of the thrombin receptor: identification of potential activators and inactivators. Parry MA, Myles T, Tschopp J, Stone SR. Biochem. J. 320 ( Pt 1) 335-341 (1996)
  23. Structural basis for inhibition promiscuity of dual specific thrombin and factor Xa blood coagulation inhibitors. Nar H, Bauer M, Schmid A, Stassen JM, Wienen W, Priepke HW, Kauffmann IK, Ries UJ, Hauel NH. Structure 9 29-37 (2001)
  24. Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator. Katz BA, Mackman R, Luong C, Radika K, Martelli A, Sprengeler PA, Wang J, Chan H, Wong L. Chem. Biol. 7 299-312 (2000)
  25. New insights into the regulation of the blood clotting cascade derived from the X-ray crystal structure of bovine meizothrombin des F1 in complex with PPACK. Martin PD, Malkowski MG, Box J, Esmon CT, Edwards BF. Structure 5 1681-1693 (1997)
  26. Crystal structure of the human alpha-thrombin-haemadin complex: an exosite II-binding inhibitor. Richardson JL, Kröger B, Hoeffken W, Sadler JE, Pereira P, Huber R, Bode W, Fuentes-Prior P. EMBO J. 19 5650-5660 (2000)
  27. Engineering inhibitors highly selective for the S1 sites of Ser190 trypsin-like serine protease drug targets. Katz BA, Sprengeler PA, Luong C, Verner E, Elrod K, Kirtley M, Janc J, Spencer JR, Breitenbucher JG, Hui H, McGee D, Allen D, Martelli A, Mackman RL. Chem. Biol. 8 1107-1121 (2001)
  28. Molecular basis for the inhibition of human alpha-thrombin by the macrocyclic peptide cyclotheonamide A. Maryanoff BE, Qiu X, Padmanabhan KP, Tulinsky A, Almond HR, Andrade-Gordon P, Greco MN, Kauffman JA, Nicolaou KC, Liu A. Proc. Natl. Acad. Sci. U.S.A. 90 8048-8052 (1993)
  29. Crystal structure of a biosynthetic sulfo-hirudin complexed to thrombin. Liu CC, Brustad E, Liu W, Schultz PG. J. Am. Chem. Soc. 129 10648-10649 (2007)
  30. Changes in interactions in complexes of hirudin derivatives and human alpha-thrombin due to different crystal forms. Priestle JP, Rahuel J, Rink H, Tones M, Grütter MG. Protein Sci. 2 1630-1642 (1993)
  31. Evidence for common structural changes in thrombin induced by active-site or exosite binding. Parry MA, Stone SR, Hofsteenge J, Jackman MP. Biochem. J. 290 ( Pt 3) 665-670 (1993)
  32. Fragment-Based flexible ligand docking by evolutionary optimization. Budin N, Majeux N, Caflisch A. Biol. Chem. 382 1365-1372 (2001)
  33. The dual role of thrombin's anion-binding exosite-I in the recognition and cleavage of the protease-activated receptor 1. Myles T, Le Bonniec BF, Stone SR. Eur. J. Biochem. 268 70-77 (2001)
  34. Structure-function analysis of Yersinia pestis YopM's interaction with alpha-thrombin to rule on its significance in systemic plague and to model YopM's mechanism of binding host proteins. Hines J, Skrzypek E, Kajava AV, Straley SC. Microb. Pathog. 30 193-209 (2001)
  35. A novel class of small functional peptides that bind and inhibit human alpha-thrombin isolated by mRNA display. Raffler NA, Schneider-Mergener J, Famulok M. Chem. Biol. 10 69-79 (2003)
  36. Elaborate manifold of short hydrogen bond arrays mediating binding of active site-directed serine protease inhibitors. Katz BA, Elrod K, Verner E, Mackman RL, Luong C, Shrader WD, Sendzik M, Spencer JR, Sprengeler PA, Kolesnikov A, Tai VW, Hui HC, Breitenbucher JG, Allen D, Janc JW. J. Mol. Biol. 329 93-120 (2003)
  37. Bivalirudin for anticoagulation in children. Rayapudi S, Torres A, Deshpande GG, Ross MP, Wohrley JD, Young G, Tarantino MD. Pediatr Blood Cancer 51 798-801 (2008)
  38. Binding of alpha-thrombin to surface-anchored platelet glycoprotein Ib(alpha) sulfotyrosines through a two-site mechanism involving exosite I. Zarpellon A, Celikel R, Roberts JR, McClintock RA, Mendolicchio GL, Moore KL, Jing H, Varughese KI, Ruggeri ZM. Proc. Natl. Acad. Sci. U.S.A. 108 8628-8633 (2011)
  39. Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site. Matthews JH, Krishnan R, Costanzo MJ, Maryanoff BE, Tulinsky A. Biophys. J. 71 2830-2839 (1996)
  40. From natural to synthetic multisite thrombin inhibitors. Lombardi A, De Simone G, Galdiero S, Staiano N, Nastri F, Pavone V. Biopolymers 51 19-39 (1999)
  41. Automated docking of highly flexible ligands by genetic algorithms: a critical assessment. Cecchini M, Kolb P, Majeux N, Caflisch A. J Comput Chem 25 412-422 (2004)
  42. Comparison of sustained antithrombotic effects of inhibitors of thrombin and factor Xa in experimental thrombosis. Biemond BJ, Friederich PW, Levi M, Vlasuk GP, Büller HR, ten Cate JW. Circulation 93 153-160 (1996)
  43. Mechanisms of Arg-Pro-Pro-Gly-Phe inhibition of thrombin. Hasan AA, Warnock M, Nieman M, Srikanth S, Mahdi F, Krishnan R, Tulinsky A, Schmaier AH. Am. J. Physiol. Heart Circ. Physiol. 285 H183-93 (2003)
  44. Synthesis, structure, and structure-activity relationships of divalent thrombin inhibitors containing an alpha-keto-amide transition-state mimetic. Krishnan R, Tulinsky A, Vlasuk GP, Pearson D, Vallar P, Bergum P, Brunck TK, Ripka WC. Protein Sci. 5 422-433 (1996)
  45. The variable region-1 from tissue-type plasminogen activator confers specificity for plasminogen activator inhibitor-1 to thrombin by facilitating catalysis: release of a kinetic block by a heterologous protein surface loop. Dekker RJ, Eichinger A, Stoop AA, Bode W, Pannekoek H, Horrevoets AJ. J. Mol. Biol. 293 613-627 (1999)
  46. Design and evaluation of novel bivalent thrombin inhibitors based on amidinophenylalanines. Steinmetzer T, Renatus M, Künzel S, Eichinger A, Bode W, Wikström P, Hauptmann J, Stürzebecher J. Eur. J. Biochem. 265 598-605 (1999)
  47. Recruiting Zn2+ to mediate potent, specific inhibition of serine proteases. Katz BA, Luong C. J. Mol. Biol. 292 669-684 (1999)
  48. Thrombin inhibitors identified by computer-assisted multiparameter design. Riester D, Wirsching F, Salinas G, Keller M, Gebinoga M, Kamphausen S, Merkwirth C, Goetz R, Wiesenfeldt M, Stürzebecher J, Bode W, Friedrich R, Thürk M, Schwienhorst A. Proc. Natl. Acad. Sci. U.S.A. 102 8597-8602 (2005)
  49. Crystallographic determination of the structures of human alpha-thrombin complexed with BMS-186282 and BMS-189090. Malley MF, Tabernero L, Chang CY, Ohringer SL, Roberts DG, Das J, Sack JS. Protein Sci. 5 221-228 (1996)
  50. Rational design and characterization of D-Phe-Pro-D-Arg-derived direct thrombin inhibitors. Figueiredo AC, Clement CC, Zakia S, Gingold J, Philipp M, Pereira PJ. PLoS ONE 7 e34354 (2012)
  51. Restoring the procofactor state of factor Va-like variants by complementation with B-domain peptides. Bunce MW, Bos MH, Krishnaswamy S, Camire RM. J. Biol. Chem. 288 30151-30160 (2013)
  52. Crystal structure of the complex of human alpha-thrombin and nonhydrolyzable bifunctional inhibitors, hirutonin-2 and hirutonin-6. Zdanov A, Wu S, DiMaio J, Konishi Y, Li Y, Wu X, Edwards BF, Martin PD, Cygler M. Proteins 17 252-265 (1993)
  53. GpIbα interacts exclusively with exosite II of thrombin. Lechtenberg BC, Freund SM, Huntington JA. J. Mol. Biol. 426 881-893 (2014)
  54. Nonbenzamidine tetrazole derivatives as factor Xa inhibitors. Quan ML, Ellis CD, He MY, Liauw AY, Woerner FJ, Alexander RS, Knabb RM, Lam PY, Luettgen JM, Wong PC, Wright MR, Wexler RR. Bioorg. Med. Chem. Lett. 13 369-373 (2003)
  55. Structural resiliency of an EGF-like subdomain bound to its target protein, thrombin. Hrabal R, Komives EA, Ni F. Protein Sci. 5 195-203 (1996)
  56. The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor. Chirgadze NY, Sall DJ, Klimkowski VJ, Clawson DK, Briggs SL, Hermann R, Smith GF, Gifford-Moore DS, Wery JP. Protein Sci. 6 1412-1417 (1997)
  57. The linkage between binding of the C-terminal domain of hirudin and amidase activity in human alpha-thrombin. de Cristofaro R, Rocca B, Bizzi B, Landolfi R. Biochem. J. 289 ( Pt 2) 475-480 (1993)
  58. Crystal structure of two new bifunctional nonsubstrate type thrombin inhibitors complexed with human alpha-thrombin. Féthière J, Tsuda Y, Coulombe R, Konishi Y, Cygler M. Protein Sci. 5 1174-1183 (1996)
  59. Enzymic O-sulfation of tyrosine residues in hirudins by sulfotransferase from Eubacterium A-44. Muramatsu R, Nukui E, Sukesada A, Misawa S, Komatsu Y, Okayama T, Wada K, Morikawa T, Hayashi H, Kobashi K. Eur. J. Biochem. 223 243-248 (1994)
  60. X-ray and spectrophotometric studies of the binding of proflavin to the S1 specificity pocket of human alpha-thrombin. Conti E, Rivetti C, Wonacott A, Brick P. FEBS Lett. 425 229-233 (1998)
  61. Functionality map analysis of the active site cleft of human thrombin. Grootenhuis PD, Karplus M. J. Comput. Aided Mol. Des. 10 1-10 (1996)
  62. The fibrinogen anion-binding exosite of thrombin is necessary for induction of rises in intracellular calcium and prostacyclin production in endothelial cells. Ngaiza JR, Manley G, Grulich-Henn J, Krstenansky JL, Jaffe EA. J. Cell. Physiol. 151 190-196 (1992)
  63. The methyl group of N(alpha)(Me)Arg-containing peptides disturbs the active-site geometry of thrombin, impairing efficient cleavage. Friedrich R, Steinmetzer T, Huber R, Stürzebecher J, Bode W. J. Mol. Biol. 316 869-874 (2002)
  64. Comparison of the structures of the cyclotheonamide A complexes of human alpha-thrombin and bovine beta-trypsin. Ganesh V, Lee AY, Clardy J, Tulinsky A. Protein Sci. 5 825-835 (1996)
  65. Crystallographic structure of a peptidyl keto acid inhibitor and human alpha-thrombin. Håkansson K, Tulinsky A, Abelman MM, Miller TA, Vlasuk GP, Bergum PW, Lim-Wilby MS, Brunck TK. Bioorg. Med. Chem. 3 1009-1017 (1995)
  66. Hirunorms are true hirudin mimetics. The crystal structure of human alpha-thrombin-hirunorm V complex. De Simone G, Lombardi A, Galdiero S, Nastri F, Della Morte R, Staiano N, Pedone C, Bolognesi M, Pavone V. Protein Sci. 7 243-253 (1998)
  67. Allosteric modulation of BPTI interaction with human alpha- and zeta-thrombin. De Cristofaro R, Landolfi R. Eur. J. Biochem. 260 97-102 (1999)
  68. Allosteric modulation of the activity of thrombin. Duffy EJ, Angliker H, Le Bonniec BF, Stone SR. Biochem. J. 321 ( Pt 2) 361-365 (1997)
  69. Interaction between Yersinia pestis YopM protein and human alpha-thrombin. Skrzypek E, Straley SC. Thromb. Res. 84 33-43 (1996)
  70. Late-fibrin(ogen) fragment E modulates human alpha-thrombin specificity. Bouton MC, Jandrot-Perrus M, Bezeaud A, Guillin MC. Eur. J. Biochem. 215 143-149 (1993)
  71. The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors. Chirgadze NY, Sall DJ, Briggs SL, Clawson DK, Zhang M, Smith GF, Schevitz RW. Protein Sci. 9 29-36 (2000)
  72. Expression of recombinant Hirudin in transgenic mice milk driven by the goat beta-casein promoter. Yen CH, Yang CK, Chen IC, Lin YS, Lin CS, Chu S, Tu CF. Biotechnol J 3 1067-1077 (2008)
  73. Noncompetitive inhibitor of thrombin. Koh CY, Kazimirova M, Nuttall PA, Kini RM. Chembiochem 10 2155-2158 (2009)
  74. Protein tyrosine-O-sulfation in the retina. Kanan Y, Hoffhines A, Rauhauser A, Murray A, Al-Ubaidi MR. Exp. Eye Res. 89 559-567 (2009)
  75. A steady-state competition model describes the modulating effects of thrombomodulin on thrombin inhibition by plasminogen activator inhibitor-1 in the absence and presence of vitronectin. Dekker RJ, Pannekoek H, Horrevoets AJ. Eur. J. Biochem. 270 1942-1951 (2003)
  76. Effect of poly(phosphate) anions on glyceraldehyde-3-phosphate dehydrogenase structure and thermal aggregation: comparison with influence of poly(sulfoanions). Semenyuk PI, Muronetz VI, Haertlé T, Izumrudov VA. Biochim. Biophys. Acta 1830 4800-4805 (2013)
  77. Human alpha-thrombin inhibition by the highly selective compounds N-ethoxycarbonyl-D-Phe-Pro-alpha-azaLys p-nitrophenyl ester and N-carbobenzoxy-Pro-alpha-azaLys p-nitrophenyl ester: a kinetic, thermodynamic and X-ray crystallographic study. De Simone G, Balliano G, Milla P, Gallina C, Giordano C, Tarricone C, Rizzi M, Bolognesi M, Ascenzi P. J. Mol. Biol. 269 558-569 (1997)
  78. Design, synthesis and evaluation of graftable thrombin inhibitors for the preparation of blood-compatible polymer materials. Salvagnini C, Michaux C, Remiche J, Wouters J, Charlier P, Marchand-Brynaert J. Org. Biomol. Chem. 3 4209-4220 (2005)
  79. Heterocyclic thrombin inhibitors. Part 1: design and synthesis of amidino-phenoxy quinoline derivatives. Ries UJ, Priepke HW, Hauel NH, Haaksma EE, Stassen JM, Wienen W, Nar H. Bioorg. Med. Chem. Lett. 13 2291-2295 (2003)
  80. Interaction of thrombin with antithrombin, heparin cofactor II, and protein C inhibitor. Whinna HC, Church FC. J. Protein Chem. 12 677-688 (1993)
  81. Synthesis of potential thrombin inhibitors. Incorporation of tartaric acid templates as P2 proline mimetics. Dahlgren A, Brånalt J, Kvarnström I, Nilsson I, Musil D, Samuelsson B. Bioorg. Med. Chem. 10 1567-1580 (2002)
  82. Atomic structures of two nitroxide spin labels complexed with human thrombin: comparison with solution studies. Nienaber VL, Berliner LJ. J Protein Chem 19 129-137 (2000)
  83. Factor Xa: simulation studies with an eye to inhibitor design. Daura X, Haaksma E, van Gunsteren WF. J. Comput. Aided Mol. Des. 14 507-529 (2000)
  84. Letter Multiple inhibitory kinetics reveal an allosteric interplay among thrombin functional sites. Zavyalova E, Kopylov A. Thromb. Res. 135 212-216 (2015)
  85. Novel non-covalent thrombin inhibitors incorporating P(1) 4,5,6,7-tetrahydrobenzothiazole arginine side chain mimetics. Marinko P, Krbavcic A, Mlinsek G, Solmajer T, Bakija AT, Stegnar M, Stojan J, Kikelj D. Eur J Med Chem 39 257-265 (2004)
  86. Structural basis of RGD-hirudin binding to thrombin: Tyr3 and five C-terminal residues are crucial for inhibiting thrombin activity. Huang Y, Zhang Y, Zhao B, Xu Q, Zhou X, Song H, Yu M, Mo W. BMC Struct. Biol. 14 26 (2014)
  87. The crystal structure of alpha-thrombin-hirunorm IV complex reveals a novel specificity site recognition mode. Lombardi A, De Simone G, Nastri F, Galdiero S, Della Morte R, Staiano N, Pedone C, Bolognesi M, Pavone V. Protein Sci. 8 91-95 (1999)
  88. Thrombin inhibitor design: X-ray and solution studies provide a novel P1 determinant. Nienaber VL, Boxrud PD, Berliner LJ. J Protein Chem 19 327-333 (2000)
  89. Avathrin: a novel thrombin inhibitor derived from a multicopy precursor in the salivary glands of the ixodid tick, Amblyomma variegatum. Iyer JK, Koh CY, Kazimirova M, Roller L, Jobichen C, Swaminathan K, Mizuguchi J, Iwanaga S, Nuttall PA, Chan MY, Kini RM. FASEB J. 31 2981-2995 (2017)
  90. Neutron and X-ray crystallographic analysis of the human α-thrombin-bivalirudin complex at pD 5.0: protonation states and hydration structure of the enzyme-product complex. Yamada T, Kurihara K, Ohnishi Y, Tamada T, Tomoyori K, Masumi K, Tanaka I, Kuroki R, Niimura N. Biochim. Biophys. Acta 1834 1532-1538 (2013)
  91. Rational design of hirulog-type inhibitors of thrombin. Egner U, Hoyer GA, Schleuning WD. J. Comput. Aided Mol. Des. 8 479-490 (1994)
  92. Selective boron-containing thrombin inhibitors--X-ray analysis reveals surprising binding mode. von Matt A, Ehrhardt C, Burkhard P, Metternich R, Walkinshaw M, Tapparelli C. Bioorg. Med. Chem. 8 2291-2303 (2000)
  93. Structure of a novel thrombin inhibitor with an uncharged D-amino acid as P1 residue. Friedrich R, Riester D, Göttig P, Thürk M, Schwienhorst A, Bode W. Eur J Med Chem 43 1330-1335 (2008)
  94. The complete N-terminal extension of heparin cofactor II is required for maximal effectiveness as a thrombin exosite 1 ligand. Boyle AJ, Roddick LA, Bhakta V, Lambourne MD, Junop MS, Liaw PC, Weitz JI, Sheffield WP. BMC Biochem. 14 6 (2013)
  95. Thrombin-bound conformation of a cyclic anticoagulant peptide using transferred nuclear Overhauser effect (NOE), distance geometry, and NOE simulations. Ning Q, Ripoll DR, Szewczuk Z, Konishi Y, Ni F. Biopolymers 34 1125-1137 (1994)
  96. Hirunorms, novel hirudin-like direct thrombin inhibitors. Cappiello M, Vilardo PG, Del Corso A, Mura U. Gen. Pharmacol. 30 565-568 (1998)
  97. Identification of a substrate-like cleavage-resistant thrombin inhibitor from the saliva of the flea Xenopsylla cheopis. Lu S, Tirloni L, Oliveira MB, Bosio CF, Nardone GA, Zhang Y, Hinnebusch BJ, Ribeiro JM, Andersen JF. J Biol Chem 297 101322 (2021)
  98. Application of profile fitting method to neutron time-of-flight protein single crystal diffraction data collected at the iBIX. Yano N, Yamada T, Hosoya T, Ohhara T, Tanaka I, Kusaka K. Sci Rep 6 36628 (2016)
  99. Chemically modified thrombin and anhydrothrombin that differentiate macromolecular substrates of thrombin. Hosokawa K, Ohnishi T, Kawakami A, Wakabayashi S, Koide T. J. Thromb. Haemost. 3 2703-2711 (2005)
  100. Letter Fibrinogen Milano IV (A alpha 16 Arg-->His): characterization of its abnormal interaction with human alpha-thrombin. De Cristofaro R, Furlan M, Landolfi R. Biochem. J. 302 ( Pt 2) 623-624 (1994)
  101. Outer surface lipoproteins from the Lyme disease spirochete exploit the molecular switch mechanism of the complement protease C1s. Garrigues RJ, Thomas S, Leong JM, Garcia BL. J Biol Chem 298 102557 (2022)


Related citations provided by authors (3)

  1. Refined Structure of the Hirudin-Thrombin Complex. Rydel TJ, Tulinsky A, Bode W, Huber R J. Mol. Biol. 221 583- (1991)
  2. The Structure of a Complex of Recombinant Hirudin and Human Alpha-Thrombin. Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C, Fenton /II JW Science 249 277- (1990)
  3. The Refined 1.9 Angstroms Crystal Structure of Human Alpha-Thrombin: Interaction with D-Phe-Pro-Arg Chloromethylketone and Significance of the Tyr-Pro-Pro-Trp Insertion Segment. Bode W, Mayr I, Baumann U, Huber R, Stone SR, Hofsteenge J EMBO J. 8 3467- (1989)

Quick links