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PDBsum entry 1avg
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Complex (blood coagulation/inhibitor)
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PDB id
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1avg
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Contents |
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41 a.a.
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259 a.a.
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142 a.a.
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of the thrombin complex with triabin, A lipocalin-Like exosite-Binding inhibitor derived from a triatomine bug.
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Authors
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P.Fuentes-Prior,
C.Noeske-Jungblut,
P.Donner,
W.D.Schleuning,
R.Huber,
W.Bode.
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Ref.
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Proc Natl Acad Sci U S A, 1997,
94,
11845-11850.
[DOI no: ]
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PubMed id
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Abstract
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Triabin, a 142-residue protein from the saliva of the blood-sucking triatomine
bug Triatoma pallidipennis, is a potent and selective thrombin inhibitor. Its
stoichiometric complex with bovine alpha-thrombin was crystallized, and its
crystal structure was solved by Patterson search methods and refined at 2.6-A
resolution to an R value of 0.184. The analysis revealed that triabin is a
compact one-domain molecule essentially consisting of an eight-stranded
beta-barrel. The eight strands A to H are arranged in the order A-C-B-D-E-F-G-H,
with the first four strands exhibiting a hitherto unobserved up-up-down-down
topology. Except for the B-C inversion, the triabin fold exhibits the regular
up-and-down topology of lipocalins. In contrast to the typical ligand-binding
lipocalins, however, the triabin barrel encloses a hydrophobic core intersected
by a unique salt-bridge cluster. Triabin interacts with thrombin exclusively via
its fibrinogen-recognition exosite. Surprisingly, most of the interface
interactions are hydrophobic. A prominent exception represents thrombin's
Arg-77A side chain, which extends into a hydrophobic triabin pocket forming
partially buried salt bridges with Glu-128 and Asp-135 of the inhibitor. The
fully accessible active site of thrombin in this complex is in agreement with
its retained hydrolytic activity toward small chromogenic substrates. Impairment
of thrombin's fibrinogen converting activity or of its thrombomodulin-mediated
protein C activation capacity upon triabin binding is explained by usage of
overlapping interaction sites of fibrinogen, thrombomodulin, and triabin on
thrombin. These data demonstrate that triabin inhibits thrombin via a novel and
unique mechanism that might be of interest in the context of potential
therapeutic applications.
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Figure 2.
Fig. 2. Stereoview of the triabin ribbon. The eight strands A
to H forming the  - barrel are
shown as yellow arrows, the N- and the^ C-terminal surface
helices are shown as green helical ribbons, and the connecting
loops are shown as green ropes. A few aromatic^ side chains, as
well as the polar residues involved in the internal salt-bridge
cluster, are shown with all nonhydrogen atoms. The^ view is,
similar as in Fig. 1, approximately along the barrel axis of
triabin  i.e.,
through the more narrow barrel opening (front) toward the wider
opening of the calyx (back). The figure was made^ with SETOR (8).
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Figure 4.
Fig. 4. Closed-up stereo-view of the interaction interface
between bovine thrombin and triabin. The contacting segments of
thrombin (blue) and triabin (yellow) are shown as  -carbon
traces, and^ only the more important side chains are given with
all atoms. Water molecules are omitted for the sake of
simplicity. Orientation is similar to that seen in Figs. 1 and
2. The figure was made^ with SETOR (8).
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