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PII S1050-1738(01)00140-2 TCM
New Insight into How Tissue Factor
Allosterically Regulates Factor VIIa
Charles Eigenbrot* and Daniel Kirchhofer
Factor VIIa (FVIIa) is the coagulation protease responsible for starting
a cascade of proteolytic events that lead to thrombin generation, and
hence, to ﬁbrin deposition and platelet activation. As such, it has
attracted interest as a target for clinical anticoagulant therapy. Com-
mensurate with the critical importance of maintaining balance
between thrombosis and hemostasis and FVIIa’s place at the beginning
of the coagulation process, FVIIa is subject to a variety of biological
and biochemical control mechanisms, among them allosteric inﬂu-
ences exerted by cofactors, substrates, and inhibitors. Essential for the
proteolytic activity of FVIIa is its cofactor, Tissue Factor (TF). Major
progress in elucidating the key inﬂuence of TF was made when the
TF·FVIIa structure was determined in 1996. However, a molecular
explanation of an important aspect of TF’s inﬂuence—its effect on the
active site—was not available until the recent determination of a FVII
zymogen structure. In this review we discuss the signiﬁcance of
unprecedented differences between these two structures in understand-
ing the regulation of this important enzyme. (Trends Cardiovasc Med
2002;12:19–26). © 2002, Elsevier Science Inc.
Charles Eigenbrot and Daniel Kirchhofer are from the Departments of Protein Engineering
and Physiology, Genentech, Inc., South San Francisco, CA.
* Address correspondence to: C. Eigenbrot, Department of Protein Engineering, Genentech,
Inc., 1 DNA Way, South San Francsico, CA 94080, USA. Tel.: (ϩ1) 650-225-2106; fax: (ϩ1) 650-
225-3734; e-mail: firstname.lastname@example.org.
© 2002, Elsevier Science Inc. All rights reserved. 1050-1738/02/$-see front matter