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PDBsum entry 1bth
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Complex (serine protease/inhibitor)
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PDB id
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1bth
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Contents |
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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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The thrombin e192q-Bpti complex reveals gross structural rearrangements: implications for the interaction with antithrombin and thrombomodulin.
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Authors
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A.Van de locht,
W.Bode,
R.Huber,
B.F.Le bonniec,
S.R.Stone,
C.T.Esmon,
M.T.Stubbs.
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Ref.
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Embo J, 1997,
16,
2977-2984.
[DOI no: ]
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PubMed id
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Abstract
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Previous crystal structures of thrombin indicate that the 60-insertion loop is a
rigid moiety that partially occludes the active site, suggesting that this
structural feature plays a decisive role in restricting thrombin's specificity.
This restricted specificity is typified by the experimental observation that
thrombin is not inhibited by micromolar concentrations of basic pancreatic
trypsin inhibitor (BPTI). Surprisingly, a single atom mutation in thrombin
(E192Q) results in a 10(-8) M affinity for BPTI. The crystal structure of human
thrombin mutant E192Q has been solved in complex with BPTI at 2.3 A resolution.
Binding of the Kunitz inhibitor is accompanied by gross structural
rearrangements in thrombin. In particular, thrombin's 60-loop is found in a
significantly different conformation. Concomitant reorganization of other
surface loops that surround the active site, i.e. the 37-loop, the 148-loop and
the 99-loop, is observed. Thrombin can therefore undergo major structural
reorganization upon strong ligand binding. Implications for the interaction of
thrombin with antithrombin and thrombomodulin are discussed.
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Figure 1.
Figure 1 Stereo view of the complex formed between human
thrombin E192Q (cyan) and BPTI (red). View is from the north
side with thrombin's 60-loop facing the viewer, i.e. rotated by
90° along x compared with thrombin's standard orientation shown
in Figure 3A. Disulfide bridges are displayed as yellow
connections. Figure prepared using MOLSCRIPT (Kraulis, 1991).
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Figure 3.
Figure 3 Changes upon BPTI binding. (A) Stereo view of thrombin
in its standard orientation, i.e. with the active site cleft
facing the viewer and the 60-loop to the north. The unaltered
core of thrombin is shown with its molecular surface. Colour
coding indicates surface curvature with concave regions in blue
and convex regions in white. Loops whose position is affected
upon BPTI binding are depicted as rods. Colour coding is green
for PPACK -thrombin and orange for BPTI -thrombin. Residues of
the catalytic triad and Gln192 are also shown. Figure produced
with Grasp (Nicholls et al., 1993). (B) Close up of the
alterations in the 60- and 39-loops upon BPTI binding. Colour
coding is as in (A). Thin blue lines indicate the unaltered
thrombin core.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
Embo J
(1997,
16,
2977-2984)
copyright 1997.
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Secondary reference #1
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Title
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The ornithodorin-Thrombin crystal structure, A key to the tap enigma?
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Authors
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A.Van de locht,
M.T.Stubbs,
W.Bode,
T.Friedrich,
C.Bollschweiler,
W.Höffken,
R.Huber.
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Ref.
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Embo J, 1996,
15,
6011-6017.
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PubMed id
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Secondary reference #2
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Title
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Two heads are better than one: crystal structure of the insect derived double domain kazal inhibitor rhodniin in complex with thrombin.
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Authors
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A.Van de locht,
D.Lamba,
M.Bauer,
R.Huber,
T.Friedrich,
B.Kröger,
W.Höffken,
W.Bode.
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Ref.
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Embo J, 1995,
14,
5149-5157.
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PubMed id
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Secondary reference #3
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Title
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The refined 1.9 a crystal structure of human alpha-Thrombin: interaction with d-Phe-Pro-Arg chloromethylketone and significance of the tyr-Pro-Pro-Trp insertion segment.
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Authors
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W.Bode,
I.Mayr,
U.Baumann,
R.Huber,
S.R.Stone,
J.Hofsteenge.
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Ref.
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Embo J, 1989,
8,
3467-3475.
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PubMed id
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