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  1. Article ; Online: A simple method to resolve rate constants when the binding mechanism obeys induced fit or conformational selection.

    Di Cera, Enrico

    The Journal of biological chemistry

    2024  Volume 300, Issue 4, Page(s) 107131

    Abstract: Many interactions involving a ligand and its molecular target are studied by rapid kinetics using a stopped-flow apparatus. Information obtained from these studies is often limited to a single, saturable relaxation that is insufficient to resolve all ... ...

    Abstract Many interactions involving a ligand and its molecular target are studied by rapid kinetics using a stopped-flow apparatus. Information obtained from these studies is often limited to a single, saturable relaxation that is insufficient to resolve all independent rate constants even for a two-step mechanism of binding obeying induced fit (IF) or conformational selection (CS). We introduce a simple method of general applicability where this limitation is overcome. The method accurately reproduces the rate constants for ligand binding to the serine protease thrombin determined independently from the analysis of multiple relaxations. Application to the inactive zymogen precursor of thrombin, prethrombin-2, resolves all rate constants for a binding mechanism of IF or CS from a single, saturable relaxation. Comparison with thrombin shows that the prethrombin-2 to thrombin conversion enhances ligand binding to the active site not by improving accessibility through the value of k
    MeSH term(s) Thrombin/metabolism ; Thrombin/chemistry ; Kinetics ; Protein Binding ; Humans ; Protein Conformation ; Ligands ; Enzyme Precursors/metabolism ; Enzyme Precursors/chemistry ; Prothrombin/metabolism ; Prothrombin/chemistry
    Chemical Substances Thrombin (EC 3.4.21.5) ; Ligands ; Enzyme Precursors ; Prothrombin (9001-26-7)
    Language English
    Publishing date 2024-03-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2024.107131
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Pass the 12-LOX!

    Di Cera, Enrico

    Blood

    2023  Volume 142, Issue 14, Page(s) 1180–1181

    MeSH term(s) Humans ; Cryoelectron Microscopy ; Cytoplasm ; Lipoxygenases
    Chemical Substances Lipoxygenases (EC 1.13.11.-)
    Language English
    Publishing date 2023-10-02
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2023021939
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  3. Book: Proteases in health and disease

    DiCera, Enrico

    (Progress in molecular biology and translational science ; 99)

    2011  

    Author's details ed. by Enrico Di Cera
    Series title Progress in molecular biology and translational science ; 99
    Collection
    Language English
    Size XII, 313 S. : Ill.
    Publisher Elsevier AP
    Publishing place Amsterdam u.a.
    Publishing country Netherlands
    Document type Book
    HBZ-ID HT016757583
    ISBN 978-0-12-385504-6 ; 0-12-385504-7
    Database Catalogue ZB MED Medicine, Health

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    Uc I Zs 357 -99- verfügbar in Königswinter Königswinter

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  4. Article: "For the Furtherance of Research"

    Eissenberg, Joel C / Jacobs, Christine K / Di Cera, Enrico

    Missouri medicine

    2023  Volume 120, Issue 5, Page(s) 351–353

    MeSH term(s) Humans ; Universities ; Medicine ; Molecular Biology
    Language English
    Publishing date 2023-10-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 427362-x
    ISSN 0026-6620
    ISSN 0026-6620
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  5. Article ; Online: Thrombin has dual trypsin-like and chymotrypsin-like specificity.

    Stojanovski, Bosko M / Pelc, Leslie A / Di Cera, Enrico

    Journal of thrombosis and haemostasis : JTH

    2023  Volume 22, Issue 4, Page(s) 1009–1015

    Abstract: Background: The residue at the site of activation of protein C is Arg in all species except the ray-finned fish, where it is Trp. This feature raises the question of whether thrombin is the physiological activator of protein C across vertebrates.: ... ...

    Abstract Background: The residue at the site of activation of protein C is Arg in all species except the ray-finned fish, where it is Trp. This feature raises the question of whether thrombin is the physiological activator of protein C across vertebrates.
    Objectives: To establish if thrombin can cleave at Trp residues.
    Methods: The activity of wild-type thrombin and mutant D189S was tested with a library of chromogenic substrates and toward wild-type protein C and mutants carrying substitutions at the site of cleavage.
    Results: Thrombin has trypsin-like and chymotrypsin-like specificity and cleaves substrates at Arg or Trp residues. Cleavage at Arg is preferred, but cleavage at Trp is significant and comparable with that of chymotrypsin. The D189S mutant of thrombin has broad specificity and cleaves at basic and aromatic residues without significant preference. Thrombin also cleaves natural substrates at Arg or Trp residues, showing activity toward protein C across vertebrates, including the ray-finned fish. The rate of activation of protein C in the ray-finned fish is affected by the sequence preceding Trp at the scissile bond.
    Conclusion: The results provide a possible solution for the paradoxical presence of a Trp residue at the site of cleavage of protein C in ray-finned fish and support thrombin as the physiological activator of protein C in all vertebrates. The dual trypsin-like and chymotrypsin-like specificity of thrombin suggests that the spectrum of physiological substrates of this enzyme is broader currently assumed.
    MeSH term(s) Animals ; Trypsin/chemistry ; Trypsin/metabolism ; Thrombin/metabolism ; Chymotrypsin/chemistry ; Chymotrypsin/metabolism ; Protein C/metabolism ; Substrate Specificity ; Kinetics ; Binding Sites
    Chemical Substances Trypsin (EC 3.4.21.4) ; Thrombin (EC 3.4.21.5) ; Chymotrypsin (EC 3.4.21.1) ; Protein C
    Language English
    Publishing date 2023-12-30
    Publishing country England
    Document type Journal Article
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1016/j.jtha.2023.12.026
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    Zs.MO 295: Show issues

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  6. Article ; Online: Monitoring prothrombin activation in plasma through loss of Förster resonance energy transfer.

    Stojanovski, Bosko M / Di Cera, Enrico

    Journal of thrombosis and haemostasis : JTH

    2023  Volume 21, Issue 7, Page(s) 1769–1778

    Abstract: Background: Current assays that monitor thrombin generation in plasma rely on fluorogenic substrates to follow the kinetics of zymogen activation, which may be complicated by substrate cleavage from other proteases. In addition, these assays depend on ... ...

    Abstract Background: Current assays that monitor thrombin generation in plasma rely on fluorogenic substrates to follow the kinetics of zymogen activation, which may be complicated by substrate cleavage from other proteases. In addition, these assays depend on activation following cleavage at the prothrombin R320 site and fail to report the cleavage at the alternative R271 site, leading to the shedding of the auxiliary Gla and kringle domains of prothrombin.
    Objectives: To develop a plasma assay that directly monitors prothrombin activation independent of fluorogenic substrate hydrolysis.
    Methods: Cleavage at the R271 site of prothrombin is monitored through loss of Förster resonance energy transfer in plasma coagulated along the extrinsic or intrinsic pathway.
    Results: The availability of factor (F)V in plasma strongly influences the rate of prothrombin activation. The rate of thrombin formation is equally perturbed in FV or prothrombin-depleted plasma, implicating that the thrombin-catalyzed feedback reactions that amplify the coagulation response play an important role in generating sufficient amounts of FVa required for the assembly of prothrombinase. Congenital deficiencies in FVIII and FIX significantly slow down cleavage at R271 in plasma coagulated along the extrinsic and intrinsic pathways. Prothrombin activation in FXI-deficient plasma is only perturbed when coagulation is triggered along the intrinsic pathway.
    Conclusion: The Förster resonance energy transfer assay enables direct monitoring of prothrombin activation through cleavage at R271 without the need for fluorogenic substrates. The assay is sensitive enough to assess how deficiencies in coagulation factors affect thrombin formation.
    MeSH term(s) Humans ; Prothrombin/chemistry ; Thrombin/metabolism ; Fluorescence Resonance Energy Transfer ; Fluorescent Dyes ; Blood Coagulation Factors ; Factor Xa/metabolism
    Chemical Substances Prothrombin (9001-26-7) ; Thrombin (EC 3.4.21.5) ; Fluorescent Dyes ; Blood Coagulation Factors ; Factor Xa (EC 3.4.21.6)
    Language English
    Publishing date 2023-03-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1016/j.jtha.2023.03.008
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  7. Article ; Online: Mechanisms of ligand binding.

    Di Cera, Enrico

    Biophysics reviews

    2020  Volume 1, Issue 1, Page(s) 11303

    Abstract: Many processes in chemistry and biology involve interactions of a ligand with its molecular target. Interest in the mechanism governing such interactions has dominated theoretical and experimental analysis for over a century. The interpretation of ... ...

    Abstract Many processes in chemistry and biology involve interactions of a ligand with its molecular target. Interest in the mechanism governing such interactions has dominated theoretical and experimental analysis for over a century. The interpretation of molecular recognition has evolved from a simple rigid body association of the ligand with its target to appreciation of the key role played by conformational transitions. Two conceptually distinct descriptions have had a profound impact on our understanding of mechanisms of ligand binding. The first description, referred to as induced fit, assumes that conformational changes follow the initial binding step to optimize the complex between the ligand and its target. The second description, referred to as conformational selection, assumes that the free target exists in multiple conformations in equilibrium and that the ligand selects the optimal one for binding. Both descriptions can be merged into more complex reaction schemes that better describe the functional repertoire of macromolecular systems. This review deals with basic mechanisms of ligand binding, with special emphasis on induced fit, conformational selection, and their mathematical foundations to provide rigorous context for the analysis and interpretation of experimental data. We show that conformational selection is a surprisingly versatile mechanism that includes induced fit as a mathematical special case and even captures kinetic properties of more complex reaction schemes. These features make conformational selection a dominant mechanism of molecular recognition in biology, consistent with the rich conformational landscape accessible to biological macromolecules being unraveled by structural biology.
    Language English
    Publishing date 2020-12-08
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2688-4089
    ISSN (online) 2688-4089
    DOI 10.1063/5.0020997
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Book ; Conference proceedings: 10 years of the Gibbs Conference on Biothermodynamics

    DiCera, Enrico

    (Biophysical chemistry ; 64,1/3 : Special issue)

    1997  

    Title variant Ten years of the Gibbs Conference on Biothermodynamics
    Event/congress Gibbs Conference on Biothermodynamics (1987-1997)
    Author's details ed. by E. di Cera
    Series title Biophysical chemistry ; 64,1/3 : Special issue
    Collection
    Keywords Biochemistry / congresses ; Thermodynamics / congresses
    Language English
    Size 294 S. : graph. Darst.
    Publisher Elsevier
    Publishing place Amsterdam u.a.
    Publishing country Netherlands
    Document type Book ; Conference proceedings
    HBZ-ID HT007493265
    Database Catalogue ZB MED Medicine, Health

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    Zs A 1147 -64- not available for loan Zeitschriften-Lesesaal

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  9. Article ; Online: Comparative sequence analysis of vitamin K-dependent coagulation factors.

    Stojanovski, Bosko M / Di Cera, Enrico

    Journal of thrombosis and haemostasis : JTH

    2022  Volume 20, Issue 12, Page(s) 2837–2849

    Abstract: Background: Prothrombin, protein C, and factors VII, IX, and X are vitamin K (VK)-dependent coagulation proteins that play an important role in the initiation, amplification, and subsequent attenuation of the coagulation response. Blood coagulation ... ...

    Abstract Background: Prothrombin, protein C, and factors VII, IX, and X are vitamin K (VK)-dependent coagulation proteins that play an important role in the initiation, amplification, and subsequent attenuation of the coagulation response. Blood coagulation evolved in the common vertebrate ancestor as a specialization of the complement system and immune response, which in turn bear close evolutionary ties with developmental enzyme cascades. There is currently no comprehensive analysis of the evolutionary changes experienced by these coagulation proteins during the radiation of vertebrates and little is known about conservation of residues that are important for zymogen activation and catalysis.
    Objectives: To characterize the conservation level of functionally important residues among VK-dependent coagulation proteins from different vertebrate lineages.
    Methods: The conservation level of residues important for zymogen activation and catalysis was analyzed in >1600 primary sequences of VK-dependent proteins.
    Results: Functionally important residues are most conserved in prothrombin and least conserved in protein C. Some of the most profound functional modifications in protein C occurred in the ancestor of bony fish when the basic residue in the activation site was replaced by an aromatic residue. Furthermore, during the radiation of placental mammals from marsupials, protein C acquired a cysteine-rich insert that introduced an additional disulfide in the EGF1 domain and evolved a proprotein convertase cleavage site in the activation peptide linker that also became significantly elongated.
    Conclusions: Sequence variabilities at functionally important residues may lead to interspecies differences in the zymogen activation and catalytic properties of orthologous VK-dependent proteins.
    MeSH term(s) Pregnancy ; Animals ; Female ; Vitamin K/metabolism ; Prothrombin/metabolism ; Protein C ; Placenta ; Blood Coagulation Factors/genetics ; Blood Coagulation Factors/metabolism ; Sequence Analysis ; Mammals/metabolism
    Chemical Substances Vitamin K (12001-79-5) ; Prothrombin (9001-26-7) ; Protein C ; Blood Coagulation Factors
    Language English
    Publishing date 2022-10-11
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.15897
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  10. Article ; Online: Role of sequence and position of the cleavage sites in prothrombin activation.

    Stojanovski, Bosko M / Di Cera, Enrico

    The Journal of biological chemistry

    2021  Volume 297, Issue 2, Page(s) 100955

    Abstract: In the penultimate step of the coagulation cascade, the multidomain vitamin-K-dependent zymogen prothrombin is converted to thrombin by the prothrombinase complex composed of factor Xa, cofactor Va, and phospholipids. Activation of prothrombin requires ... ...

    Abstract In the penultimate step of the coagulation cascade, the multidomain vitamin-K-dependent zymogen prothrombin is converted to thrombin by the prothrombinase complex composed of factor Xa, cofactor Va, and phospholipids. Activation of prothrombin requires cleavage at two residues, R271 and R320, along two possible pathways generating either the intermediate prethrombin-2 (following initial cleavage at R271) or meizothrombin (following initial cleavage at R320). The former pathway is preferred in the absence of and the latter in the presence of cofactor Va. Several mechanisms have been proposed to explain this preference, but the role of the sequence and position of the sites of cleavage has not been thoroughly investigated. In this study, we engineered constructs where the sequences
    MeSH term(s) Blood Coagulation ; Kinetics ; Prothrombin
    Chemical Substances Prothrombin (9001-26-7) ; prethrombins (9070-19-3)
    Language English
    Publishing date 2021-07-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2021.100955
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