'''Coagulation Factor VII Zymogen (EGF2/Protease) in Complex with Inhibitory Exosite Peptide A-183'''
===Coagulation Factor VII Zymogen (EGF2/Protease) in Complex with Inhibitory Exosite Peptide A-183===
==Overview==
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BACKGROUND: Coagulation factor VIIa (FVIIa) contains a Trypsin-like serine protease domain and initiates the cascade of proteolytic events leading to Thrombin activation and blood clot formation. Vascular injury allows formation of the complex between circulating FVIIa and its cell surface bound obligate cofactor, Tissue Factor (TF). Circulating FVIIa is nominally activated but retains zymogen-like character and requires TF in order to complete the zymogen-to-enzyme transition. The manner in which TF exerts this effect is unclear. The structure of TF/FVIIa is known. Knowledge of the zymogen structure is helpful for understanding the activation transition in this system. RESULTS: The 2 A resolution crystal structure of a zymogen form of FVII comprising the EGF2 and protease domains is revealed in a complex with the exosite binding inhibitory peptide A-183 and a vacant active site. The activation domain, which includes the N terminus, differs in ways beyond those that are expected for zymogens in the Trypsin family. There are large differences in the TF binding region. An unprecedented 3 residue shift in registration between beta strands B2 and A2 in the C-terminal beta barrel and hydrogen bonds involving Glu154 provide new insight into conformational changes accompanying zymogen activation, TF binding, and enzymatic competence. CONCLUSIONS: TF-mediated allosteric control of the activity of FVIIa can be rationalized. The reregistering beta strand connects the TF binding region and the N-terminal region. The zymogen registration allows H bonds that prevent the N terminus from attaining a key salt bridge with the active site. TF binding may influence an equilibrium by selecting the enzymatically competent registration.
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{{ABSTRACT_PUBMED_11470437}}
==About this Structure==
==About this Structure==
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[[Category: Beta-strand]]
[[Category: Beta-strand]]
[[Category: Shifted registration]]
[[Category: Shifted registration]]
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Revision as of 16:59, 1 July 2008
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