Vanderbilt University School of Medicine

Bock, Paul E. , Ph.D.
Professor of Pathology, Microbiology and Immunology
Professor of Medicine

Lab Url: N/A

Phone Number: 615-343-9863


Bock, Paul's picture

Office Address   Mailing Address

1205 Stallworth Rehabilitation Hospital

C3321A Medical Center North 37232-2561

Research Keywords
Blood coagulation, Fibrinolysis, Enzyme mechanisms, Protein structure, Biochemistry, Biophysics, Fluorescence spectroscopy, Bacterial virulence factors, Pathology, Infectious diseases, Cardiovascular diseases,Bacteria,Biochemistry,Enzyme action,Pathology,Protein Structure,Spectroscopy

Research Description
Research in this laboratory is focused on molecular mechanisms of human blood coagulation and fibrinolysis and their roles in cardiovascular and infectious diseases. Biochemical and biophysical techniques are being used to determine how the proteolytic enzymes of blood coagulation and fibrinolysis are regulated through interactions with specific physiological and pathological proteins, and the membrane surfaces of vascular cells. Present work focuses on three areas: (1) The mechanism by which coagulation factor Va regulates the formation of the active blood clotting proteinase, thrombin, from its inactive precursor, prothrombin, and the mechanisms of thrombin regulation; (2) The mechanism of non-proteolytic activation of prothrombin by the Streptococcus aureus protein, staphylocoagulase and its homologs, and their roles in the molecular pathology of infections of heart valves in acute bacterial endocarditis; and (3) The mechanism of activation of plasminogen by the streptococcal protein, streptokinase, which is the basis for its critical role as a virulence factor in life-threatening streptococcal infections. Fluorescence spectroscopy, protein chemistry, enzyme kinetics, and molecular biology approaches are being used to define the roles of protein conformational changes and the assembly of macromolecular complexes in these mechanisms. The goal of the research is to develop molecular descriptions of these systems, which are necessary for development of new therapeutic approaches for treatment of thrombosis, and for inhibitory targeting of bacterial pathogenicity factors that usurp the human coagulation and fibrinolytic systems to propagate infectious diseases.

Kroh, HK, Panizzi, P, Tchaikovski, S, Baird, TR, Wei, N, Krishnaswamy, S, Tans, G, Rosing, J, Furie, B, Furie, BC, Bock, PE. Active site-labeled prothrombin inhibits prothrombinase in vitro and thrombosis in vivo. J Biol Chem, 286(26), 23345-56, 2011.

Laha, M, Panizzi, P, Nahrendorf, M, Bock, PE. Engineering streptokinase for generation of active site-labeled plasminogen analogs. Anal Biochem, 415(2), 105-15, 2011.

Wiles, KG, Panizzi, P, Kroh, HK, Bock, PE. Skizzle is a novel plasminogen- and plasmin-binding protein from Streptococcus agalactiae that targets proteins of human fibrinolysis to promote plasmin generation. J Biol Chem, 285(27), 21153-64, 2010. PMCID:2898333

Kroh, HK, Panizzi, P, Bock, PE. Von Willebrand factor-binding protein is a hysteretic conformational activator of prothrombin. Proc Natl Acad Sci U S A, 106(19), 7786-91, 2009. PMCID:2683071

Tharp, AC, Laha, M, Panizzi, P, Thompson, MW, Fuentes-Prior, P, Bock, PE. Plasminogen substrate recognition by the streptokinase-plasminogen catalytic complex is facilitated by Arg253, Lys256, and Lys257 in the streptokinase {beta}-domain and kringle 5 of the substrate. J Biol Chem, 284(29), 19511-21, 2009. PMCID:2740577

Smith, SB, Verhamme, IM, Sun, MF, Bock, PE, Gailani, D. Characterization of Novel Forms of Coagulation Factor XIa: independence of factor XIa subunits in factor IX activation. J Biol Chem, 283(11), 6696-705, 2008. PMCID:2633474

Verhamme, IM, Bock, PE. Rapid-reaction kinetic characterization of the pathway of streptokinase.plasmin catalytic complex formation. J Biol Chem, , , 2008. PMCID:2533780

Bock, PE, Panizzi, P, Verhamme, IM. Exosites in the substrate specificity of blood coagulation reactions. J Thromb Haemost, 5 Suppl 1, 81-94, 2007. PMCID:2291348

Hacisalihoglu, A, Panizzi, P, Bock, PE, Camire, RM, Krishnaswamy, S. Restricted Active Site Docking by Enzyme-bound Substrate Enforces the Ordered Cleavage of Prothrombin by Prothrombinase. J Biol Chem, 282(45), 32974-82, 2007. PMCID:2292459

Kroh, HK, Tans, G, Nicolaes, GA, Rosing, J, Bock, PE. Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation. J Biol Chem, 282(22), 16095-104, 2007. PMCID:2292469

Munnix, IC, Kuijpers, MJ, Auger, J, Thomassen, CM, Panizzi, P, van Zandvoort, MA, Rosing, J, Bock, PE, Watson, SP, Heemskerk, JW. Segregation of platelet aggregatory and procoagulant microdomains in thrombus formation: regulation by transient integrin activation. Arterioscler Thromb Vasc Biol, 27(11), 2484-90, 2007. PMCID:2376762

Panizzi, P, Boxrud, PD, Verhamme, IM, Bock, PE. Binding of the COOH-terminal lysine residue of streptokinase to plasmin(ogen) kringles enhances formation of the streptokinase.plasmin(ogen) catalytic complexes. J Biol Chem, 281(37), 26774-8, 2006. PMCID:2291350

Panizzi, P, Friedrich, R, Fuentes-Prior, P, Kroh, HK, Briggs, J, Tans, G, Bode, W, Bock, PE. Novel fluorescent prothrombin analogs as probes of staphylocoagulase-prothrombin interactions. J Biol Chem, 281(2), 1169-78, 2006. PMCID:2292460

Panizzi, P, Friedrich, R, Fuentes-Prior, P, Richter, K, Bock, PE, Bode, W. Fibrinogen substrate recognition by staphylocoagulase.(pro)thrombin complexes. J Biol Chem, 281(2), 1179-87, 2006. PMCID:2291351

Bean, RR, Verhamme, IM, Bock, PE. Role of the streptokinase alpha-domain in the interactions of streptokinase with plasminogen and plasmin. J Biol Chem, 280(9), 7504-10, 2005. PMCID:2292463

Bianchini, EP, Orcutt, SJ, Panizzi, P, Bock, PE, Krishnaswamy, S. Ratcheting of the substrate from the zymogen to proteinase conformations directs the sequential cleavage of prothrombin by prothrombinase. Proc Natl Acad Sci U S A, 102(29), 10099-104, 2005. PMCID:1174926

Ogawa, T, Verhamme, IM, Sun, MF, Bock, PE, Gailani, D. Exosite-mediated substrate recognition of factor IX by factor XIa. The factor XIa heavy chain is required for initial recognition of factor IX. J Biol Chem, 280(25), 23523-30, 2005. PMCID:2292466

Boxrud, PD, Bock, PE. Coupling of conformational and proteolytic activation in the kinetic mechanism of plasminogen activation by streptokinase. J Biol Chem, 279(35), 36642-9, 2004.

Boxrud, PD, Verhamme, IM, Bock, PE. Resolution of conformational activation in the kinetic mechanism of plasminogen activation by streptokinase. J Biol Chem, 279(35), 36633-41, 2004.

Panizzi, P, Friedrich, R, Fuentes-Prior, P, Bode, W, Bock, PE. The staphylocoagulase family of zymogen activator and adhesion proteins. Cell Mol Life Sci, 61(22), 2793-8, 2004. PMCID:2291352

Verhamme, IM, Bock, PE, Jackson, CM. The preferred pathway of glycosaminoglycan-accelerated inactivation of thrombin by heparin cofactor II. J Biol Chem, 279(11), 9785-95, 2004.

Anderson, PJ, Bock, PE. Role of prothrombin fragment 1 in the pathway of regulatory exosite I formation during conversion of human prothrombin to thrombin. J Biol Chem, 278(45), 44489-95, 2003.

Anderson, PJ, Nesset, A, Bock, PE. Effects of activation peptide bond cleavage and fragment 2 interactions on the pathway of exosite I expression during activation of human prethrombin 1 to thrombin. J Biol Chem, 278(45), 44482-8, 2003.

Bedsted, Tina, Swanson, Richard, Chuang, Yung-Jen, Bock, Paul E, Bj??rk, Ingemar, Olson, Steven T, . Heparin and calcium ions dramatically enhance antithrombin reactivity with factor IXa by generating new interaction exosites.. Biochemistry, 42, 8143-52, 2003.

Flanagan, John J, Chen, Jui-Chang, Miao, Yiwei, Shao, Yuanlong, Lin, Jialing, Bock, Paul E, Johnson, Arthur E, . Signal recognition particle binds to ribosome-bound signal sequences with fluorescence-detected subnanomolar affinity that does not diminish as the nascent chain lengthens.. J Biol Chem, 278, 18628-37, 2003.

Verhamme, Ingrid M, Olson, Steven T, Tollefsen, Douglas M, Bock, Paul E. Binding of exosite ligands to human thrombin. Re-evaluation of allosteric linkage between thrombin exosites I and II. J Biol Chem, 277(9), 6788-98, 2002.

Anderson, P J, Bock, P E. Biotin derivatives of D-Phe-Pro-Arg-CH2Cl for active-site-specific labeling of thrombin and other serine proteinases. Anal Biochem, 296(2), 254-61, 2001.

Boxrud, P D, Verhamme, I M, Fay, W P, Bock, P E. Streptokinase triggers conformational activation of plasminogen through specific interactions of the amino-terminal sequence and stabilizes the active zymogen conformation. J Biol Chem, 276(28), 26084-9, 2001.

Johnson, A E, Chen, J C, Flanagan, J J, Miao, Y, Shao, Y, Lin, J, Bock, P E, . Structure, function, and regulation of free and membrane-bound ribosomes: the view from their substrates and products.. Cold Spring Harb Symp Quant Biol, 66, 531-41, 2001.

Monteiro, R. Q., Bock, P. E., Bianconi, M. L., and Zingali, R. B. Characterization of Bothrojaracin Interacion with Human Prothrombin. Protein Science, 10, 1897-1904, 2001.

Pekovich, S R, Bock, P E, Hoover, R L. Thrombin-thrombomodulin activation of protein C facilitates the activation of progelatinase A. FEBS Lett, 494(1-2), 129-32, 2001.

Anderson, PJ, Nesset, A, Dharmawardana, KR, Bock, PE. Role of proexosite I in factor Va-dependent substrate interactions of prothrombin activation. J Biol Chem, 275(22), 16435-42, 2000.

Anderson, PJ, Nesset, A, Dharmawardana, KR, Bock, PE. Characterization of proexosite I on prothrombin. J Biol Chem, 275(22), 16428-34, 2000.

Boxrud, P D, Bock, P E. Streptokinase binds preferentially to the extended conformation of plasminogen through lysine binding site and catalytic domain interactions. Biochemistry, 39(45), 13974-81, 2000.

Boxrud, P D, Fay, W P, Bock, P E. Streptokinase binds to human plasmin with high affinity, perturbs the plasmin active site, and induces expression of a substrate recognition exosite for plasminogen. J Biol Chem, 275(19), 14579-89, 2000.

Dharmawardana, K R, Olson, S T, Bock, P E. Role of regulatory exosite I in binding of thrombin to human factor V, factor Va, factor Va subunits, and activation fragments. J Biol Chem, 274(26), 18635-43, 1999.

Dharmawardana, K R, Bock, P E. Demonstration of exosite I-dependent interactions of thrombin with human factor V and factor Va involving the factor Va heavy chain: analysis by affinity chromatography employing a novel method for active-site-selective immobilization of serine proteinases. Biochemistry, 37(38), 13143-52, 1998.

Bock, P E, Olson, S T, Bj??rk, I. Inactivation of thrombin by antithrombin is accompanied by inactivation of regulatory exosite I. J Biol Chem, 272(32), 19837-45, 1997.

Bock, P E, Day, D E, Verhamme, I M, Bernardo, M M, Olson, S T, Shore, J D. Analogs of human plasminogen that are labeled with fluorescence probes at the catalytic site of the zymogen. Preparation, characterization, and interaction with streptokinase. J Biol Chem, 271(2), 1072-80, 1996.

Hogg, PJ, Jackson, CM, Labanowski, JK, Bock, PE. Binding of fibrin monomer and heparin to thrombin in a ternary complex alters the environment of the thrombin catalytic site, reduces affinity for hirudin, and inhibits cleavage of fibrinogen. J Biol Chem, 271(42), 26088-95, 1996.

Olson, ST, Bock, PE, Kvassman, J, Shore, JD, Lawrence, DA, Ginsburg, D, Bj??rk, I. Role of the catalytic serine in the interactions of serine proteinases with protein inhibitors of the serpin family. Contribution of a covalent interaction to the binding energy of serpin-proteinase complexes. J Biol Chem, 270(50), 30007-17, 1995.

Olson, ST, Stephens, AW, Hirs, CH, Bock, PE, Bj??rk, I. Kinetic characterization of the proteinase binding defect in a reactive site variant of the serpin, antithrombin. Role of the P1'' residue in transition-state stabilization of antithrombin-proteinase complex formation. J Biol Chem, 270(17), 9717-24, 1995.

Bock, P E. Thioester peptide chloromethyl ketones: reagents for active site-selective labeling of serine proteinases with spectroscopic probes. Methods Enzymol, 222, 478-503, 1993.

Bj??rk, I, Ylinenj??rvi, K, Olson, ST, Bock, PE. Conversion of antithrombin from an inhibitor of thrombin to a substrate with reduced heparin affinity and enhanced conformational stability by binding of a tetradecapeptide corresponding to the P1 to P14 region of the putative reactive bond loop of the inhibitor. J Biol Chem, 267(3), 1976-82, 1992.

Olson, ST, Bock, PE, Sheffer, R. Quantitative evaluation of solution equilibrium binding interactions by affinity partitioning: application to specific and nonspecific protein-heparin interactions. Arch Biochem Biophys, 286(2), 533-45, 1991.

Carlisle, TL, Bock, PE, Jackson, CM. Kinetic intermediates in prothrombin activation. Bovine prethrombin 1 conversion to thrombin by factor X. J Biol Chem, 265(35), 22044-55, 1990.

Bock, PE, Craig, PA, Olson, ST, Singh, P. Isolation of human blood coagulation alpha-factor Xa by soybean trypsin inhibitor-sepharose chromatography and its active-site titration with fluorescein mono-p-guanidinobenzoate. Arch Biochem Biophys, 273(2), 375-88, 1989.

Shore, JD, Day, DE, Bock, PE, Olson, ST. Acceleration of surface-dependent autocatalytic activation of blood coagulation factor XII by divalent metal ions. Biochemistry, 26(8), 2250-8, 1987.

Postdoctoral Position Available

Postdoctoral Position Details
A Postdoctoral Research position is available to investigate the mechanisms and regulation of blood coagulation and
fibrinolysis reactions with protein chemistry, enzyme kinetics, and fluorescence spectroscopy approaches. Applicants
must be US citizens or permanent residents. Interested individuals who are recent Ph.D. degree graduates in biochemistry, biophysics,
chemistry, or biology should send a copy of their curriculum vitae and arrange for two letters of recommendation to be
sent to:Dr. Paul E. BOCK Vanderbilt University School of Medicine Department of Pathology
C-3321A Medical Center North Nashville, TN 37232-2561 Tel. (615)343-9863

Updated Date

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