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PDBsum entry 4nzq
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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 linker connecting the two kringles plays a key role in prothrombin activation.
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Authors
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N.Pozzi,
Z.Chen,
L.A.Pelc,
D.B.Shropshire,
E.Di cera.
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Ref.
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Proc Natl Acad Sci U S A, 2014,
111,
7630-7635.
[DOI no: ]
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PubMed id
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Abstract
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The zymogen prothrombin is proteolytically converted by factor Xa to the active
protease thrombin in a reaction that is accelerated >3,000-fold by cofactor
Va. This physiologically important effect is paradigmatic of analogous
cofactor-dependent reactions in the coagulation and complement cascades, but its
structural determinants remain poorly understood. Prothrombin has three linkers
connecting the N-terminal Gla domain to kringle-1 (Lnk1), the two kringles
(Lnk2), and kringle-2 to the C-terminal protease domain (Lnk3). Recent
developments indicate that the linkers, and particularly Lnk2, confer on the
zymogen significant flexibility in solution and enable prothrombin to sample
alternative conformations. The role of this flexibility in the context of
prothrombin activation was tested with several deletions. Removal of Lnk2 in
almost its entirety (ProTΔ146-167) drastically reduces the enhancement of
thrombin generation by cofactor Va from >3,000-fold to 60-fold because of a
significant increase in the rate of activation in the absence of cofactor.
Deletion of Lnk2 mimics the action of cofactor Va and offers insights into how
prothrombin is activated at the molecular level. The crystal structure of
ProTΔ146-167 reveals a contorted architecture where the domains are not
vertically stacked, kringle-1 comes within 9 Å of the protease domain, and the
Gla-domain primed for membrane binding comes in contact with kringle-2. These
findings broaden our molecular understanding of a key reaction of the blood
coagulation cascade where cofactor Va enhances activation of prothrombin by
factor Xa by compressing Lnk2 and morphing prothrombin into a conformation
similar to the structure of ProTΔ146-167.
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Secondary reference #1
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Title
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Crystal structure of prethrombin-1
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Authors
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Z.Chen,
L.A.Pelc,
E.Di cera.
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Ref.
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proc natl acad sci usa, 2010,
107,
19278.
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Secondary reference #2
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Title
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Structure of bovine prothrombin fragment 1 refined at 2.25 a resolution.
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Authors
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T.P.Seshadri,
A.Tulinsky,
E.Skrzypczak-Jankun,
C.H.Park.
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Ref.
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J Mol Biol, 1991,
220,
481-494.
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PubMed id
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