Crystal Structure of Thrombin in Complex with S-Variegin: Insights of a Novel Mechanism of Inhibition and Design of Tunable Thrombin Inhibitors Page: 2
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A Novel Mechanism of Thrombin Inhibition
Figure 1. Structure of thrombin:s-variegin complex. (A) Thrombin (yellow) shown in the classical orientation in ribbon (without s-variegin).
Side chains of catalytic triad, TAspI02, THis57 and TSerl95 are shown in sticks (green). The 60-loop, autolysis loop and Na+-binding loop are circled in
brown, cyan and green, respectively. Parts of thrombin forming the anion-binding exosite-I and exosite-ll are circled in blue and purple, respectively.
(B) Surface representation of thrombin (yellow) in the same orientation as (a). Locations of active site specificity pocket, non-prime and prime subsites
are indicated by arrows. (C) The structure of thrombin (yellow) in the same orientation as above shown in complex with s-variegin (pink) together
with its electron density map (2Fo-Fc) shown contoured at 0.9c. (D) Surface representation of thrombin in complex with s-variegin (pink).
is one of the main targets for inhibition, owing to its pivotal role in
coagulation. Several direct thrombin inhibitors, such as hirudin
, hirulog- 1/bivalirudin , argatroban  and dabigatran
, are currently available in the market. Among them, hirudin
and hirulog-1 /bivalirudin are both developed from hematopha-
gous parasites and their success continues to inspire the search for
more novel anticoagulants from these sources [14,15].
: PLoS ONE I www.plosone.org
Recently, we described variegin, a novel, fast and tight-binding
competitive inhibitor of thrombin (refers to the a form of thrombin
unless otherwise stated) isolated from the tropical bont tick,
Ambdyomma variegatum . Like hirudin/hirulog, variegin targets
the thrombin catalytic site and exosite-I. However, unlike other
naturally occurring thrombin inhibitors, variegin interacts with the
thrombin prime subsites in addition to exosite-I . Variegin has
October 2011 1 Volume 6 1 Issue 10 1 e26367
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Koh, Cho Yeow; Kumar, Sundramurthy; Kazimirova, Maria; Nuttall, Patricia A.; Radhakrishnan, Uvaraj P.; Kim, Seongcheol et al. Crystal Structure of Thrombin in Complex with S-Variegin: Insights of a Novel Mechanism of Inhibition and Design of Tunable Thrombin Inhibitors, article, October 2011; [San Francisco, California]. (digital.library.unt.edu/ark:/67531/metadc287041/m1/2/: accessed November 14, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Arts and Sciences.