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| [[1irh]] – hTFPI-1 kunitz domain III - NMR<br /> | | [[1irh]] – hTFPI-1 kunitz domain III - NMR<br /> |
| [[1tfx]] – hTFPI-1 kunitz domain II + trypsin <br /> | | [[1tfx]] – hTFPI-1 kunitz domain II + trypsin <br /> |
| | [[6bx8]] – hTFPI-1 kunitz domain I (mutant) + trypsin <br /> |
| [[1zr0]] – hTFPI-2 kunitz domain I + trypsin <br /> | | [[1zr0]] – hTFPI-2 kunitz domain I + trypsin <br /> |
| [[5nmv]] – hTFPI-1 kunitz domain I + antibody <br /> | | [[5nmv]] – hTFPI-1 kunitz domain I + antibody <br /> |
Revision as of 10:21, 26 February 2020
| Function
Tissue factor pathway inhibitor (TFPI) is a protease inhibitor which inhibits coagulation factor Xa and VIIa[1]. TFPI contains three Kunitz domains. The Kunitz domain is disulfide-rich and is arranged to form a twisted two-stranded antiparallel β sheet followed by an α helix. Kunitz I and II domains inhibit VIIa coagulation factor while Kunitz II domain inhibits Xa. Kunitz III domains probably involved in the interactions with lipoproteins.
Relevance
The expression of hTFPI-2 in tumors is inversely related to their malignancy[2]. TFPI inhibitors are investigated as therapeutic agents agains hemophilia[3].
Structural highlights
In the complex of TFPI-2 and trypsin, hydrophobic residues of TFPI-2 interact with hydrophobic patch of trypsin. An Arg residue which is the P1 residue of TFPI-2 interacts with Asp - the S1 residue of trypsin[4]. Ca coordination site. Water molecules are shown as red spheres.
- ↑ Kato H. Tissue factor pathway inhibitor; its structure, function and clinical significance. Pol J Pharmacol. 1996 Jan-Feb;48(1):67-72. PMID:9112630
- ↑ Sierko E, Wojtukiewicz MZ, Kisiel W. The role of tissue factor pathway inhibitor-2 in cancer biology. Semin Thromb Hemost. 2007 Oct;33(7):653-9. PMID:18000791 doi:https://dx.doi.org/10.1055/s-2007-991532
- ↑ Peterson JA, Maroney SA, Mast AE. Targeting TFPI for hemophilia treatment. Thromb Res. 2016 May;141 Suppl 2:S28-30. doi: 10.1016/S0049-3848(16)30359-0. PMID:27207418 doi:https://dx.doi.org/10.1016/S0049-3848(16)30359-0
- ↑ Schmidt AE, Chand HS, Cascio D, Kisiel W, Bajaj SP. Crystal structure of Kunitz domain 1 (KD1) of tissue factor pathway inhibitor-2 in complex with trypsin. Implications for KD1 specificity of inhibition. J Biol Chem. 2005 Jul 29;280(30):27832-8. Epub 2005 Jun 2. PMID:15932872 doi:10.1074/jbc.M504105200
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3D Structures of tissue factor pathway inhibitor
Updated on 26-February-2020
Tissue factor pathway inhibitor domains: kunitz I 29-118; kunitz II 121-178; kunitz III 210-270
1adz – hTFPI-1 kunitz domain II (mutant) – human - NMR
1irh – hTFPI-1 kunitz domain III - NMR
1tfx – hTFPI-1 kunitz domain II + trypsin
6bx8 – hTFPI-1 kunitz domain I (mutant) + trypsin
1zr0 – hTFPI-2 kunitz domain I + trypsin
5nmv – hTFPI-1 kunitz domain I + antibody
4dtg – hTFPI-1 kunitz domain II + antibody
4bqd – hTFPI-1 kunitz domain I + peptide
References
