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Structural insights into thrombolytic activity of destabilase from medicinal leech.
Marin, Egor; Kornilov, Daniil A; Bukhdruker, Sergey S; Aleksenko, Vladimir A; Manuvera, Valentin A; Zinovev, Egor V; Kovalev, Kirill V; Shevtsov, Mikhail B; Talyzina, Anna A; Bobrovsky, Pavel A; Kuzmichev, Pavel K; Mishin, Alexey V; Gushchin, Ivan Y; Lazarev, Vassili N; Borshchevskiy, Valentin I.
Afiliación
  • Marin E; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Kornilov DA; Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
  • Bukhdruker SS; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Aleksenko VA; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Manuvera VA; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Zinovev EV; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Kovalev KV; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.
  • Shevtsov MB; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Talyzina AA; EMBL Outstation Hamburg, c/o DESY, Hamburg, Germany.
  • Bobrovsky PA; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Kuzmichev PK; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Mishin AV; Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
  • Gushchin IY; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Lazarev VN; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.
  • Borshchevskiy VI; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
Sci Rep ; 13(1): 6641, 2023 04 24.
Article en En | MEDLINE | ID: mdl-37095116
Destabilase from the medical leech Hirudo medicinalis belongs to the family of i-type lysozymes. It has two different enzymatic activities: microbial cell walls destruction (muramidase activity), and dissolution of the stabilized fibrin (isopeptidase activity). Both activities are known to be inhibited by sodium chloride at near physiological concentrations, but the structural basis remains unknown. Here we present two crystal structures of destabilase, including a 1.1 Å-resolution structure in complex with sodium ion. Our structures reveal the location of sodium ion between Glu34/Asp46 residues, which were previously recognized as a glycosidase active site. While sodium coordination with these amino acids may explain inhibition of the muramidase activity, its influence on previously suggested Ser49/Lys58 isopeptidase activity dyad is unclear. We revise the Ser49/Lys58 hypothesis and compare sequences of i-type lysozymes with confirmed destabilase activity. We suggest that the general base for the isopeptidase activity is His112 rather than Lys58. pKa calculations of these amino acids, assessed through the 1 µs molecular dynamics simulation, confirm the hypothesis. Our findings highlight the ambiguity of destabilase catalytic residues identification and build foundations for further research of structure-activity relationship of isopeptidase activity as well as structure-based protein design for potential anticoagulant drug development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hirudo medicinalis / Sanguijuelas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Rep Año: 2023 Tipo del documento: Article País de afiliación: Rusia Pais de publicación: Reino Unido
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hirudo medicinalis / Sanguijuelas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Rep Año: 2023 Tipo del documento: Article País de afiliación: Rusia Pais de publicación: Reino Unido