Reconstructing the binding site of factor Xa in trypsin reveals ligand-induced structural plasticity

Journal of Molecular Biology

Volumn 325, Issue 5, 2003, Pages 963-977

  Reyda, Sabine ^a   Sohn, Christian ^a   Klebe, Gerhard ^a   Rall, Kathrin ^b,c   Ullmann, Dirk ^b,d   Jakubke, Hans Dieter ^b   Stubbs, Milton T ^a,e  

^a PHILIPPS UNIVERSITY MARBURG   (Germany)

^b UNIVERSITY OF LEIPZIG   (Germany)

^c MAX PLANCK INSTITUTE OF MICROSTRUCTURE PHYSICS   (Germany)

^d EVOTEC BioSystems AG   (Germany)

^e MARTIN LUTHER UNIVERSITY HALLE WITTENBERG   (Germany)

Author keywords

Co factor activation; Crystal structure; Drug design; Inhibitor; Molecular mimicry

Indexed keywords

BENZAMIDE DERIVATIVE; BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING FACTOR 10A INHIBITOR; CYSTEINE; LIGAND; PHENYLALANINE; TRYPSIN; TRYPSIN INHIBITOR;

ARTICLE; BINDING SITE; CONTROLLED STUDY; DISULFIDE BOND; DRUG PROTEIN BINDING; GEOMETRY; HUMAN; ISOMERISM; NONHUMAN; PLASTICITY; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; PROTEIN VARIANT; SITE DIRECTED MUTAGENESIS; YEAST;

EID: 0037474479     PISSN: 00222836     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0022-2836(02)01337-2     Document Type: Article

References (80)

1. Cushman D.W., Cheung H.S., Sabo E.F., Ondetti M.A. Design of potent competitive inhibitors of Angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry. 16:1977;5484-5491.
2. Heinemann U., Illing G., Oschkinat H. High-throughput three-dimensional protein structure determination. Curr. Opin. Biotechnol. 12:2001;348-354.
3. Hauptmann J., Sturzebecher J. Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. Thromb. Res. 93:1999;203-241.
4. Engh R.A., Brandstetter H., Sucher G., Eichinger A., Baumann U., Bode W., et al. Enzyme flexibility, solvent and "weak" interactions characterize thrombin-ligand interactions: implications for drug design. Structure. 4:1996;1353-1362.
5. Malikayil J.A., Burkhart J.P., Schreuder H.A., Broersma R.J. Jr, Tardif C., Kutcher L.W. 3rd, et al. Molecular design and characterization of an alpha-thrombin inhibitor containing a novel P1 moiety. Biochemistry. 36:1997;1034-1040.
6. Tucker T.J., Brady S.F., Lumma W.C., Lewis S.D., Gardell S.J., Naylor-Olsen A.M., et al. Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position. J. Med. Chem. 41:1998;3210-3219.
7. Stubbs M.T., Bode W. Crystal structures of thrombin and thrombin complexes as a framework for antithrombotic drug design. Perspectives Drug Disc. Des. 1:1993;431-452.
8. Faull, A. W., Mayo, C. M., Preston, J. & Stocker, A. (1996). Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents. Patent Nr. WO, 9610022.
9. Padmanabhan K., Padmanabhan K.P., Tulinsky A., Park C.H., Bode W., Huber R., et al. Structure of human des(1-45) factor Xa at 2.2 Å resolution. J. Mol. Biol. 232:1993;947-966.
10. Brandstetter H., Kuhne A., Bode W., Huber R., von der Saal W., Wirthensohn K., Engh R.A. X-Ray structure of active site-inhibited clotting factor Xa. Implications for drug design and substrate recognition. J. Biol. Chem. 271:1996;29988-29992.
11. Kamata K., Kawamoto H., Honma T., Iwama T., Kim S.H. Structural basis for chemical inhibition of human blood coagulation factor Xa. Proc. Natl Acad. Sci. USA. 95:1998;6630-6635.
12. Adler M., Davey D.D., Phillips G.B., Kim S.H., Jancarik J., Rumennik G., et al. Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa. Biochemistry. 39:2000;12534-12542.
13. Nar H., Bauer M., Schmid A., Stassen J.M., Wienen W., Priepke H.W., et al. Structural basis for inhibition promiscuity of dual specific thrombin and factor Xa blood coagulation inhibitors. Structure, (Camb.). 9:2001;29-37.
14. Maignan S., Guilloteau J.P., Pouzieux S., Choi-Sledeski Y.M., Becker M.R., Klein S.I., et al. Crystal structures of human factor Xa complexed with potent inhibitors. J. Med. Chem. 43:2000;3226-3232.
15. Stubbs M.T., Huber R., Bode W. Crystal structures of factor Xa specific inhibitors in complex with trypsin: structural grounds for inhibition of factor Xa and selectivity against thrombin. FEBS Letters. 375:1995;103-107.
16. Gabriel B., Stubbs M.T., Bergner A., Hauptmann J., Bode W., Sturzebecher J., Moroder L. Design of benzamidine-type inhibitors of factor Xa. J. Med. Chem. 41:1998;4240-4250.
17. Renatus M., Bode W., Huber R., Sturzebecher J., Stubbs M.T. Structural and functional analyses of benzamidine-based inhibitors in complex with trypsin: implications for the inhibition of factor Xa, tPA, and urokinase. J. Med. Chem. 41:1998;5445-5456.
18. Whitlow M., Arnaiz D.O., Buckman B.O., Davey D.D., Griedel B., Guilford W.J., et al. Crystallographic analysis of potent and selective factor Xa inhibitors complexed to bovine trypsin. Acta Crystallog. sect. D. 55:1999;1395-1404.
19. Dudley D.A., Bunker A.M., Chi L., Cody W.L., Holland D.R., Ignasiak D.P., et al. Rational design, synthesis, and biological activity of benzoxazinones as novel factor Xa inhibitors. J. Med. Chem. 43:2000;4063-4070.
20. Han Q., Dominguez C., Stouten P.F., Park J.M., Duffy D.E., Galemmo R.A. Jr, et al. Design, synthesis, and biological evaluation of potent and selective amidino bicyclic factor Xa inhibitors. J. Med. Chem. 43:2000;4398-4415.
21. Pinto D.J., Orwat M.J., Wang S., Fevig J.M., Quan M.L., Amparo E., et al. Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2′-(methylsulfonyl)-[1,1′- biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa. J. Med. Chem. 44:2001;566-578.
22. Sperl S., Bergner A., Sturzebecher J., Magdolen V., Bode W., Moroder L. Urethanyl-3-amidinophenylalanine derivatives as inhibitors of factor Xa. X-Ray crystal structure of a trypsin/inhibitor complex and modeling studies. Biol. Chem. 381:2000;321-329.
23. Stubbs M.T., Reyda S., Dullweber F., Möller M., Klebe G., Dorsch D., et al. pH-dependent binding modes observed in trypsin crystals - implications for structure-based lead development. Chem. BioChem. 3:2002;246-249.
24. Hedstrom L., Szilagyi L., Rutter W.J. Converting trypsin to chymotrypsin: the role of surface loops. Science. 255:1992;1249-1253.
25. Hopfner K.P., Brandstetter H., Karcher A., Kopetzki E., Huber R., Engh R.A., Bode W. Converting blood coagulation factor IXa into factor Xa: dramatic increase in amidolytic activity identifies important active site determinants. EMBO J. 16:1997;6626-6635.
26. Hopfner K.P., Kopetzki E., Kresse G.B., Bode W., Huber R., Engh R.A. New enzyme lineages by subdomain shuffling. Proc. Natl Acad. Sci. USA. 95:1998;9813-9818.
27. Perona J.J., Tsu C.A., McGrath M.E., Craik C.S., Fletterick R.J. Relocating a negative charge in the binding pocket of trypsin. J. Mol. Biol. 230:1993;934-949.
28. Xu S., Rall K., Bordusa F. Enzymatic coupling of specific peptides at nonspecific ligation sites: effect of Asp189Glu mutation in trypsin on substrate mimetic-mediated reactions. J. Org. Chem. 66:2001;1627-1632.
29. Jackson D.Y., Burnier J., Quan C., Stanley M., Tom J., Wells J.A. A designed peptide ligase for total synthesis of ribonuclease A with unnatural catalytic residues. Science. 266:1994;243-247.
30. Stubbs M.T. Structural aspects of Factor Xa Inhibition. Curr. Pharm. Des. 2:1996;543-552.
31. Wilke M.E., Higaki J.N., Craik C.S., Fletterick R.J. Crystal structure of rat trypsin-S195C at -150 degrees C. Analysis of low activity of recombinant and semisynthetic thiol proteases. J. Mol. Biol. 219:1991;511-523.
32. Brandstetter H., Turk D., Hoeffken H.W., Grosse D., Sturzebecher J., Martin P.D., et al. Refined 2.3 Å 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. J. Mol. Biol. 226:1992;1085-1099.
33. Katz B.A., Sprengeler P.A., Luong C., Verner E., Elrod K., Kirtley M., et al. Engineering inhibitors highly selective for the S1 sites of Ser190 trypsin-like serine protease drug targets. Chem. Biol. 8:2001;1107-1121.
34. Mackman R.L., Katz B.A., Breitenbucher J.G., Hui H.C., Verner E., Luong C., et al. Exploiting subsite S1 of trypsin-like serine proteases for selectivity: potent and selective inhibitors of urokinase-type plasminogen activator. J. Med. Chem. 44:2001;3856-3871.
35. Klebe G. The use of composite crystal-field environments in molecular recognition and the de novo design of protein ligands. J. Mol. Biol. 237:1994;212-235.
36. Böhm H.J., Klebe G. What can we learn from molecular recognition in protein-ligand complexes for the design of new drugs? Angew. Chem., Int. Ed. Engl. 35:1996;2588-2614.
37. Renatus M., Bode W., Huber R., Sturzebecher J., Prasa D., Fischer S., et al. Structural mapping of the active site specificity determinants of human tissue-type plasminogen activator. Implications for the design of low molecular weight substrates and inhibitors. J. Biol. Chem. 272:1997;21713-21719.
38. Shaw K.J., Guilford W.J., Dallas J.L., Koovakkaat S.K., McCarrick M.A., Liang A., et al. (Z,Z)-2,7-Bis(4-amidinobenzylidene)cycloheptan-1-one: identification of a highly active inhibitor of blood coagulation factor Xa. J. Med. Chem. 41:1998;3551-3556.
39. Phillips G.B., Buckman B.O., Davey D.D., Eagen K.A., Guilford W.J., Hinchman J., et al. Discovery of N-[2-[5-[Amino(imino)methyl]-2-hydroxyphenoxy]-3,5-difluoro-6-[3-(4,5- dihydro-1-methyl-1H-imidazol-2-yl)phenoxy]pyridin-4-yl]-N-methylglycine (ZK-807834): a potent, selective, and orally active inhibitor of the blood coagulation enzyme factor Xa. J. Med. Chem. 41:1998;3557-3562.
40. + binding site of thrombin. J. Biol. Chem. 270:1995;22089-22092.
41. Davie E.W., Fujikawa K., Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry. 30:1991;10363-10370.
42. Giannelli F., Green P.M., Sommer S.S., Lillicrap D.P., Ludwig M., Schwaab R., et al. Haemophilia B: database of point mutations and short additions and deletions. Nucl. Acids Res. 22:1994;3534-3546. 2nd edit.
43. Bottema C.D., Ketterling R.P., Ii S., Yoon H.S., Phillips J.A. 3rd, Sommer S.S. Missense mutations and evolutionary conservation of amino acids: evidence that many of the amino acids in factor IX function as "spacer" elements. Am. J. Hum. Genet. 49:1991;820-838.
44. Roberts H.R. Molecular biology of hemophilia B. Thromb. Haemostasis. 70:1993;1-9.
45. Brandstetter H., Bauer M., Huber R., Lollar P., Bode W.X. X-Ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B. Proc. Natl Acad. Sci. USA. 92:1995;9796-9800.
46. Kolkman J.A., Christophe O.D., Lenting P.J., Mertens K. Surface loop 199-204 in blood coagulation factor IX is a cofactor-dependent site involved in macromolecular substrate interaction. J. Biol. Chem. 274:1999;29087-29093.
47. Chang J., Jin J., Lollar P., Bode W., Brandstetter H., Hamaguchi N., et al. Changing residue 338 in human factor IX from arginine to alanine causes an increase in catalytic activity. J. Biol. Chem. 273:1998;12089-12094.
48. Bajaj S.P., Schmidt A.E., Mathur A., Padmanabhan K., Zhong D., Mastri M., Fay P.J. Factor IXa:factor VIIIa interaction. helix 330-338 of factor ixa interacts with residues 558-565 and spatially adjacent regions of the a2 subunit of factor VIIIa. J. Biol. Chem. 276:2001;16302-16309.
49. Bajaj S.P. Region of factor IXa protease domain that interacts with factor VIIIa: analysis of select hemophilia B mutants. Thromb. Haemostasis. 82:1999;218-225.
50. Rudolph A.E., Porche-Sorbet R., Miletich J.P. Substitution of asparagine for arginine 347 of recombinant factor Xa markedly reduces factor Va binding. Biochemistry. 39:2000;2861-2867.
51. Rudolph A.E., Porche-Sorbet R., Miletich J.P. Definition of a factor Va binding site in factor Xa. J. Biol. Chem. 276:2001;5123-5128.
52. Pedersen A.H., Nordfang O., Norris F., Wiberg F.C., Christensen P.M., Moeller K.B., et al. Recombinant human extrinsic pathway inhibitor. Production, isolation, and characterization of its inhibitory activity on tissue factor-initiated coagulation reactions. J. Biol. Chem. 265:1990;16786-16793.
53. Silverberg S.A., Nemerson Y., Zur M. Kinetics of the activation of bovine coagulation factor X by components of the extrinsic pathway. Kinetic behavior of two-chain factor VII in the presence and absence of tissue factor. J. Biol. Chem. 252:1977;8481-8488.
54. Persson E., Kjalke M., Olsen O.H. Rational design of coagulation factor VIIa variants with substantially increased intrinsic activity. Proc. Natl Acad. Sci. USA. 98:2001;13583-13588.
55. Persson E., Bak H., Olsen O.H. Substitution of valine for leucine 305 in factor VIIa increases the intrinsic enzymatic activity. J. Biol. Chem. 276:2001;29195-29199.
56. Persson E., Nielsen L.S., Olsen O.H. Substitution of aspartic acid for methionine-306 in factor VIIa abolishes the allosteric linkage between the active site and the binding interface with tissue factor. Biochemistry. 40:2001;3251-3256.
57. Banner D.W., D'Arcy A., Chene C., Winkler F.K., Guha A., Konigsberg W.H., et al. The crystal structure of the complex of blood coagulation factor VIIa with soluble tissue factor. Nature. 380:(6569):1996;41-46.
58. Pike A.C., Brzozowski A.M., Roberts S.M., Olsen O.H., Persson E. Structure of human factor VIIa and its implications for the triggering of blood coagulation. Proc. Natl Acad. Sci. USA. 96:1999;8925-8930.
59. Osterlund M., Owenius R., Carlsson K., Carlsson U., Persson E., Lindgren M., et al. Probing inhibitor-induced conformational changes along the interface between tissue factor and factor VIIa. Biochemistry. 40:2001;9324-9328.
60. Eigenbrot C., Kirchhofer D., Dennis M.S., Santell L., Lazarus R.A., Stamos J., Ultsch M.H. The factor VII zymogen structure reveals reregistration of beta strands during activation. Structure, (Camb.). 9:2001;627-636.
61. McClintock D.K., Bell P.H. The mechanism of activation of human plasminogen by streptokinase. Biochem. Biophys. Res. Commun. 43:1971;694-702.
62. Castellino F.J. A unique enzyme-protein substrate modifier reaction: plasmin/streptokinase interaction. Trends Biochem. Sci. 1979;1-5.
63. Parry M.A., Fernandez-Catalan C., Bergner A., Huber R., Hopfner K.P., Schlott B., et al. The ternary microplasmin-staphylokinase-microplasmin complex is a proteinase-cofactor-substrate complex in action. Nature Struct. Biol. 5:1998;917-923.
64. Wang X., Lin X., Loy J.A., Tang J., Zhang X.C. Crystal structure of the catalytic domain of human plasmin complexed with streptokinase. Science. 281:1998;1662-1665.
65. Parry M.A., Zhang X.C., Bode W. Molecular mechanisms of plasminogen activation: bacterial cofactors provide clues. Trends Biochem. Sci. 25:2000;52-59.
66. Wang X., Terzyan S., Tang J., Loy J.A., Lin X., Zhang X.C. Human plasminogen catalytic domain undergoes an unusual conformational change upon activation. J. Mol. Biol. 295:2000;903-914.
67. Peisach E., Wang J., de los Santos T., Reich E., Ringe D. Crystal structure of the proenzyme domain of plasminogen. Biochemistry. 38:1999;11180-11188.
68. Huber R., Bode W. Structural basis of the activation and action of trypsin. Acc. Chem. Res. 11:1978;114-122.
69. Stubbs M.T., Renatus M., Bode W. An active zymogen: unravelling the mystery of tissue-type plasminogen activator. Biol. Chem. 379:1998;95-103.
70. Rånby M., Bergsdorf N., Nilsson T. Enzymatic properties of the one and twochain form of tissue plasminogen activator. Thromb. Res. 27:1982;175-183.
71. Bode W. The transition of bovine trypsinogen to a trypsin-like state upon strong ligand binding. II. The binding of the pancreatic trypsin inhibitor and of isoleucine-valine and of sequentially related peptides to trypsinogen and to p-guanidinobenzoate-trypsinogen. J. Mol. Biol. 127:1979;357-374.
72. Sanchez R., Pieper U., Melo F., Eswar N., Marti-Renom M.A., Madhusudhan M.S., et al. Protein structure modeling for structural genomics. Nature Struct. Biol. 7:2000;986-990.
73. Papworth C., Braman J., Wright D.A. QuikChange site directed mutagenesis. Strategies. 9:1996;3-4.
74. Hedstrom L., Lin T.Y., Fast W. Hydrophobic interactions control zymogen activation in the trypsin family of serine proteases. Biochemistry. 35:1996;4515-4523.
75. Sturzebecher J., Sturzebecher U., Vieweg H., Wagner G., Hauptmann J., Markwardt F. Synthetic inhibitors of bovine factor Xa and thrombin; comparison of their anticoagulant efficiency. Thromb. Res. 54:1989;245-252.
76. i. Biochem. J. 129:1953;197-202.
77. Otkinowski Z., Minor W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276A:1997;307-326.
78. Brünger A. X-PLOR (Version3.1). A system for X-ray Crystallography and NMR. 1992;Yale University Press, New Haven, CT.
79. Jones T.A., Zou J.Y., Cowan S.W., Kjeelgaard M. Improved methods for building protein models in electron density maps and location of errors in these models. Acta Crystallog. 47:1991;110-119.
80. Bacon G.E., Curry N.A., Wilson S.A. A crystallographic study of solid benzene by neutron diffraction. Proc. Roy. Soc. London, ser. A. 279:1964;98-110.