3D4U

Bovine thrombin-activatable fibrinolysis inhibitor (TAFIa) in complex with tick-derived carboxypeptidase inhibitor.

Summary for 3D4U

• Entry DOI: 10.2210/pdb3d4u/pdb
• Related: 1KWM 1ZLI
• Descriptor: Carboxypeptidase B2, Carboxypeptidase inhibitor, ZINC ION, ... (6 entities in total)
• Functional Keywords: protease-inhibitor complex, carboxypeptidase, glycoprotein, hydrolase, metal-binding, metalloprotease, protease, secreted, zymogen, blood coagulation, fibrinolysis, metalloenzyme inhibitor, metalloprotease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Rhipicephalus bursa; More
• Cellular location: Secreted (By similarity): Q2KIG3; Secreted: Q5EPH2
• Total number of polymer chains: 2
• Total formula weight: 44500.68

Authors

Sanglas, L.,Valnickova, Z.,Arolas, J.L.,Pallares, I.,Guevara, T.,Sola, M.,Kristensen, T.,Enghild, J.J.,Aviles, F.X.,Gomis-Ruth, F.X. (deposition date: 2008-05-15, release date: 2008-08-19, Last modification date: 2024-10-30)

Primary citation

Sanglas, L.,Valnickova, Z.,Arolas, J.L.,Pallares, I.,Guevara, T.,Sola, M.,Kristensen, T.,Enghild, J.J.,Aviles, F.X.,Gomis-Ruth, F.X.
Structure of activated thrombin-activatable fibrinolysis inhibitor, a molecular link between coagulation and fibrinolysis.
Mol.Cell, 31:598-606, 2008

PubMed Abstract: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a metallocarboxypeptidase (MCP) that links blood coagulation and fibrinolysis. TAFI hampers fibrin-clot lysis and is a pharmacological target for the treatment of thrombotic conditions. TAFI is transformed through removal of its prodomain by thrombin-thrombomodulin into TAFIa, which is intrinsically unstable and has a short half-life in vivo. Here we show that purified bovine TAFI activated in the presence of a proteinaceous inhibitor renders a stable enzyme-inhibitor complex. Its crystal structure reveals that TAFIa conforms to the alpha/beta-hydrolase fold of MCPs and displays two unique flexible loops on the molecular surface, accounting for structural instability and susceptibility to proteolysis. In addition, point mutations reported to enhance protein stability in vivo are mainly located in the first loop and in another surface region, which is a potential heparin-binding site. The protein inhibitor contacts both the TAFIa active site and an exosite, thus contributing to high inhibitory efficiency.

PubMed: 18722183
DOI: 10.1016/j.molcel.2008.05.031

Experimental method

X-RAY DIFFRACTION (1.7 Å)