Urokinase plasminogen activator (uPA) complexed with it's soluble receptor (suPAR) and the antibody against the receptor (ATN615)
uPA,suPAR：Homo sapiens (human) / ATN615：Mus musculus (mouse)
The Urokinase-type plasminogen activator (uPA) is a serine protease which binds to its cellular receptor (uPAR) with high affinity and triggers signaling cascades that are associated with tumor growth, metastasis, and inflammation. The uPA-uPAR system plays important roles in tumor biology and metastasis. Levels of soluble uPAR (suPAR) in tumor cells is known to be strongly related to a prognosis for patient survival rate. Inhibition of uPAR expression leads to inhibition of tumor cell invasiveness, prevention of metastasis, reversion of invasive tumor behavior, and increase of the duration of tumor latency. From these findings, there is a clinical interest in uPAR antagonists, which is a potential candidate inhibitor for tumor progression. Therefore, determination of the structure of uPAR was desired.
The structure shown here is the suPAR complexed with the amino-terminal fragment (ATF) of uPA and the ATN615 which is an antibody against the receptor.
ATF, which includes the uPAR binding domain of uPA, made stable complex with suPAR. ATF consists of two domains, the kringle domain and growth factor-like domain (GFD), and the latter forms the uPAR binding domain. GFD is composed of two short beta strands and connecting omega-loop, a major receptor-binding determinant.
The structure of uPAR consists of 3 domains (D1, D2, and D3). All of three domains form a concave shape with a central cone-shaped cavity where the GFD domain of uPA inserts and are involved in interaction with GFD domain. The authors of this paper compared this structure with inhibitor-bound suPAR, and indicate that uPAR greatly changes the form of binding pocket according to nature of the ligands. suPAR and uPAR has almost same affinity to uPA, so they also indicate that this structure of suPAR provides insights into binding of uPAR and uPA.
Figure 1: The structure of amino-terminal fragment (ATF) of urokinase-type plasminogen activator (uPA) complexed with it's soluble receptor (suPAR) and the ATN615 which is an antibody against the receptor in cartoon expression. The domain structure of uPA is shown in figure 2. The domain structure of uPAR is shown in figure 3.
Figure 2: The structure of amino-terminal fragment (ATF) of urokinase-type plasminogen activator (uPA) with two domains, kringle domain (orange) and grouth factor-like domain (GFD, cyan), in cartoon expression. The GFD is involved in interaction with suPAR. The residues forming disulfide bonds are shown in the ball and stick expression. The disulfide bonds were shown with red lines.
Figure 3: The structure of soluble urokinase-type plasminogen activator receptor (suPAR) with three domains, D1, D2, and D3, in cartoon expression. The D1 and D2 interact with it's ligand uPA, whereas the D3 interacts with it's antibody ATN615.
Protein Data Bank (PDB)
author: Miho Higurashi