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Loop Electrostatics Asymmetry Modulates the Preexisting Conformational Equilibrium in Thrombin.

Pozzi N, Zerbetto M, Acquasaliente L, Tescari S, Frezzato D, Polimeno A, Gohara DW, Di Cera E, De Filippis V
Biochemistry 55 3984-94 (2016)
Related entries: 1sfq, 1sg8, 1sgi, 1shh

Cited: 14 times
EuropePMC logo PMID: 27347732

Abstract

Thrombin exists as an ensemble of active (E) and inactive (E*) conformations that differ in their accessibility to the active site. Here we show that redistribution of the E*-E equilibrium can be achieved by perturbing the electrostatic properties of the enzyme. Removal of the negative charge of the catalytic Asp102 or Asp189 in the primary specificity site destabilizes the E form and causes a shift in the 215-217 segment that compromises substrate entrance. Solution studies and existing structures of D102N document stabilization of the E* form. A new high-resolution structure of D189A also reveals the mutant in the collapsed E* form. These findings establish a new paradigm for the control of the E*-E equilibrium in the trypsin fold.

Articles - 5jdu mentioned but not cited (1)

  1. Loop Electrostatics Asymmetry Modulates the Preexisting Conformational Equilibrium in Thrombin. Pozzi N, Zerbetto M, Acquasaliente L, Tescari S, Frezzato D, Polimeno A, Gohara DW, Di Cera E, De Filippis V. Biochemistry 55 3984-3994 (2016)


Reviews citing this publication (2)

  1. Structure of Coagulation Factor II: Molecular Mechanism of Thrombin Generation and Development of Next-Generation Anticoagulants. Chinnaraj M, Planer W, Pozzi N. Front Med (Lausanne) 5 281 (2018)
  2. Noncoded amino acids in protein engineering: Structure-activity relationship studies of hirudin-thrombin interaction. De Filippis V, Acquasaliente L, Pontarollo G, Peterle D. Biotechnol Appl Biochem 65 69-80 (2018)

Articles citing this publication (11)

  1. Non-canonical proteolytic activation of human prothrombin by subtilisin from Bacillus subtilis may shift the procoagulant-anticoagulant equilibrium toward thrombosis. Pontarollo G, Acquasaliente L, Peterle D, Frasson R, Artusi I, De Filippis V. J Biol Chem 292 15161-15179 (2017)
  2. Structure of prothrombin in the closed form reveals new details on the mechanism of activation. Chinnaraj M, Chen Z, Pelc LA, Grese Z, Bystranowska D, Di Cera E, Pozzi N. Sci Rep 8 2945 (2018)
  3. Role of the I16-D194 ionic interaction in the trypsin fold. Stojanovski BM, Chen Z, Koester SK, Pelc LA, Di Cera E. Sci Rep 9 18035 (2019)
  4. Residues W215, E217 and E192 control the allosteric E*-E equilibrium of thrombin. Pelc LA, Koester SK, Chen Z, Gistover NE, Di Cera E. Sci Rep 9 12304 (2019)
  5. Sodium-induced population shift drives activation of thrombin. Kahler U, Kamenik AS, Kraml J, Liedl KR. Sci Rep 10 1086 (2020)
  6. Effects of point mutations in the binding pocket of the mouse major urinary protein MUP20 on ligand affinity and specificity. Ricatti J, Acquasaliente L, Ribaudo G, De Filippis V, Bellini M, Llovera RE, Barollo S, Pezzani R, Zagotto G, Persaud KC, Mucignat-Caretta C. Sci Rep 9 300 (2019)
  7. Functional analysis of rare genetic variants in complement factor I in advanced age-related macular degeneration. Java A, Pozzi N, Schroeder MC, Hu Z, Huan T, Seddon JM, Atkinson J. Hum Mol Genet 31 3683-3693 (2022)
  8. Role of the activation peptide in the mechanism of protein C activation. Stojanovski BM, Pelc LA, Di Cera E. Sci Rep 10 11079 (2020)
  9. Staphylococcus aureus iron-regulated surface determinant B (IsdB) protein interacts with von Willebrand factor and promotes adherence to endothelial cells. Alfeo MJ, Pagotto A, Barbieri G, Foster TJ, Vanhoorelbeke K, De Filippis V, Speziale P, Pietrocola G. Sci Rep 11 22799 (2021)
  10. Exogenous human α-Synuclein acts in vitro as a mild platelet antiaggregant inhibiting α-thrombin-induced platelet activation. Acquasaliente L, Pontarollo G, Radu CM, Peterle D, Artusi I, Pagotto A, Uliana F, Negro A, Simioni P, De Filippis V. Sci Rep 12 9880 (2022)
  11. From haemadin to haemanorm: Synthesis and characterization of full-length haemadin from the leech Haemadipsa sylvestris and of a novel bivalent, highly potent thrombin inhibitor (haemanorm). Acquasaliente L, Pierangelini A, Pagotto A, Pozzi N, De Filippis V. Protein Sci 32 e4825 (2023)


Related citations provided by authors (1)

  1. Molecular dissection of Na+ binding to thrombin.. Pineda AO, Carrell CJ, Bush LA, Prasad S, Caccia S, Chen ZW, Mathews FS, Di Cera E J Biol Chem 279 31842-53 (2004)

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