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PDBsum entry 3r4l
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Blood clotting
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PDB id
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3r4l
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References listed in PDB file
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Key reference
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Title
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Remarkable extension of pai-1 half-Life surprisingly brings no changes to its structure.
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Authors
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J.Jankun,
J.Yang,
H.Zheng,
F.Q.Han,
A.Al-Senaidy,
E.Skrzypczak-Jankun.
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Ref.
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Int J Mol Med, 2012,
29,
61-64.
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PubMed id
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Abstract
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Plasminogen activator inhibitor type 1 (PAI-1) is a serpin protein, a natural
inhibitor of urokinase (uPA) and tissue plasminogen activators (tPA). By
inhibiting uPA it can block growth of the cancer tumors by suppressing
angiogenesis, while when acting on tPA in the blood it can avert conversion of
plasminogen to plasmin preventing lysis of the clot. Furthermore, blocking PAI-1
activity can protect against thrombosis. Thus PAI-1 makes great impact on human
homeostasis and is desirable for clinical application. Wild-type PAI-1
(wt-PAI-1) has a short span of activity with a t1/2 of ~2 h, being spontaneously
converted into a latent form. An enormous effort has been made to create a more
stable molecule with >600 PAI-1 variants constructed to study its
structure-function relationship. In the present study, we evaluate the structure
of the active recombinant VLHL-PAI-1 (very long half life, active >700 h)
which is glycosylated similarly to wt-PAI-1 at N232 and N288, with the extended
reactive center loop, intact engineered -S-S-bridge (Q174C, G323C) that
precludes latency without affecting structure, and can be controlled by a
reducing agent to terminate activity at will. We have already proven its
usefulness to control cancer in human cancer cells, as well as preventing clot
lysis in human whole blood and plasma and in a mouse model. Our results
demonstrate the potential therapeutic applications (topical or systemic) of this
protein in the treatment of cancer, for the trauma patients to ward off an
excessive blood loss, or for people with the PAI-1 deficiency, especially during
surgery.
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Secondary reference #1
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Title
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A novel form of the plasminogen activator inhibitor created by cysteine mutations extends its half-Life: relevance to cancer and angiogenesis.
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Authors
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J.Chorostowska-Wynimko,
R.Swiercz,
E.Skrzypczak-Jankun,
A.Wojtowicz,
S.H.Selman,
J.Jankun.
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Ref.
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Mol Cancer Ther, 2003,
2,
19-28.
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PubMed id
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Secondary reference #2
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Title
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Vlhl plasminogen activator inhibitor spontaneously reactivates from the latent to active form.
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Authors
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J.Jankun,
A.M.Aleem,
S.H.Selman,
V.Basrur,
E.Skrzypczak-Jankun.
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Ref.
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Int J Mol Med, 2009,
23,
57-63.
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PubMed id
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