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Hamostaseologie 1995; 15(01): 1-13
DOI: 10.1055/s-0038-1660901
Originalarbeit/Original Article
Schattauer GmbH

Die Raumstruktur des Thrombins: ein Wegweiser zu seinen vielfältigen Funktionen

W. Bode
1   Max-Planck-Institut für Biochemie, Martinsried
,
M. T. Stubbs
1   Max-Planck-Institut für Biochemie, Martinsried
› Author Affiliations
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Publication History

Publication Date:
26 June 2018 (online)

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Zusammenfassung

Die durch Röntgenstrukturanalyse des α-Thrombins, seiner Komplexe mit Inhibitoren und Substraten sowie mehrerer Prothrombin-Fragmente gewonnene Strukturinformation gestattet es jetzt, die vielen unterschiedlichen Funktionen des Thrombins durch seine strukturellen Eigenschaften zu erklären. Das α-Thrombin hat eine ungewöhnlich tiefe und enge Activ-site-Spalte, die durch besonders große, typische Peptidschleifen ein canyonartiges Aussehen erhält. Diese Spalte trägt ganz wesentlich zu der engen Substratspezifität des Thrombins bei. Die Thrombinoberfläche läßt sich in eine ganze Reihe strukturell und funktionell unterschiedlicher Regionen einteilen. Wie am Beispiel der Fibrinogenbindung besonders gut gezeigt werden kann, ermöglicht die Nachbarschaft der aktiven Reste zu einer hydrophoben Tasche (der sog. apolaren Bindungsregion) und zu einem alkalischen Bereich (der Fibrinogen-Erkennungsregion) die Feinabstimmung der proteolytischen Aktivität. Das Thrombin benützt diese beiden Kontaktbereiche u. a. auch bei der spezifischen Erkennung und Bindung des Hirudins, eines aus dem medizinischen Egel gewonnenen Thrombin-Inhibitors, sowie des Thrombinrezeptors. Die Verstärkung der Thrombinwechselwirkung mit dem Antithrombin III durch das Heparin läßt sich durch die Verbrückung zweier Heparinbindungsstellen am Thrombin und am Antithrombin III erklären. Die nichtproteolytischen Effekte des Thrombins mit zellulären Strukturen sind dagegen vermutlich im wesentlichen auf eine der beiden die Active-site-Spalte umgebenden Peptidschleifen zurückzuführen.

Schlüsselwörter

Thrombin - Prothrombin - Fibrinogen - Substratspezifität - Inhibition - Hirudin - Antithrombin III - Heparin - Kristallstruktur
 

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