Crystal structure of the unoccupied murine urokinase‐type plasminogen activator receptor (<scp>uPAR</scp>) reveals a tightly packed DII–DIII unit

Liu, Min; Lin, Lin; Høyer‐Hansen, Gunilla; Ploug, Michael; Li, Hanlin; Jiang, Longguang; Yuan, Cai; Li, Jinyu; Huang, Mingdong

doi:10.1002/1873-3468.13397

Cited by 4 publications

(4 citation statements)

References 78 publications

(110 reference statements)

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“…Crystalizing uPAR in a closed conformation with an empty ligand binding cavity required that the multi-domain topology was stabilized by either a non-natural disulphide bond between DI and DIII as in uPAR H 47 C – N 259 C ( Gardsvoll et al, 2011b ; Xu et al, 2012 ) or by a monoclonal antibody that bound to the flexible linker region between DI and DII ( Zhao et al, 2015 ). Attempts to determine the structure of “native” uPAR without any stabilizing agents resulted in an electron density map from which a compact structure of uPAR DIIDIII could be determined, but no electron densities corresponding to DI were traceable despite DI was present in the crystals ( Liu et al, 2019 ).…”

Section: Structure Of Uparmentioning

confidence: 99%

Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention

Leth

Ploug

2021

Front. Cell Dev. Biol.

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The interaction between the serine protease urokinase-type plasminogen activator (uPA) and its glycolipid-anchored receptor (uPAR) focalizes plasminogen activation to cell surfaces, thereby regulating extravascular fibrinolysis, cell adhesion, and migration. uPAR belongs to the Ly6/uPAR (LU) gene superfamily and the high-affinity binding site for uPA is assembled by a dynamic association of its three consecutive LU domains. In most human solid cancers, uPAR is expressed at the invasive areas of the tumor-stromal microenvironment. High levels of uPAR in resected tumors or shed to the plasma of cancer patients are robustly associated with poor prognosis and increased risk of relapse and metastasis. Over the years, a plethora of different strategies to inhibit uPA and uPAR function have been designed and investigated in vitro and in vivo in mouse models, but so far none have been implemented in the clinics. In recent years, uPAR-targeting with the intent of cytotoxic eradication of uPAR-expressing cells have nonetheless gained increasing momentum. Another avenue that is currently being explored is non-invasive imaging with specific uPAR-targeted reporter-molecules containing positron emitting radionuclides or near-infrared (NIR) florescence probes with the overarching aim of being able to: (i) localize disease dissemination using positron emission tomography (PET) and (ii) assist fluorescence guided surgery using optical imaging. In this review, we will discuss these advancements with special emphasis on applications using a small 9-mer peptide antagonist that targets uPAR with high affinity.

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Section: Structure Of Uparmentioning

confidence: 99%

Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention

Leth

Ploug

2021

Front. Cell Dev. Biol.

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“…As ligands of uPAR, uPA and vitronectin can simultaneously bind to uPAR at different binding sites 20 , 23 . uPA is a single-chain protein with a molecular weight of 54 kD that contains an N-terminal domain with an EGF-like sequence, through which uPA can bind to the three domains of uPAR by forming a large hydrophobic cavity 24 - 26 . Vitronectin, a viscous glycoprotein with a molecular weight of 75 kD, is widely found in blood and ECM and interacts with different kinds of ligands 27 , 28 .…”

Section: The Upa/upar Systemmentioning

confidence: 99%

uPAR: An Essential Factor for Tumor Development

Lv¹,

Zhao²,

Jiang³

et al. 2021

J. Cancer

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Tumorigenesis is closely related to the loss of control of many genes. Urokinase-type plasminogen activator receptor (uPAR), a glycolipid-anchored protein on the cell surface, is controlled by many factors in tumorigenesis and is expressed in many tumor tissues. In this review, we summarize the regulatory effects of the uPAR signaling pathway on processes and factors related to tumor progression, such as tumor cell proliferation, adhesion, metastasis, glycolysis, tumor microenvironment and angiogenesis. Overall, the evidence accumulated to date suggests that uPAR induction by tumor progression may be one of the most important factors affecting therapeutic efficacy. An improved understanding of the interactions between uPAR and its coreceptors in cancer will provide critical biomolecular information that may help to better predict the disease course and response to therapy.

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“…Small molecules are designed to bind in the deep hydrophobic pocket of uPAR, which accommodates the 25-residue β-hairpin from the uPA growth-factor-like domain (GFD). These strategies assume that uPAR adopts a similar structure in the apo and uPA-bound states, but there is evidence that uPAR is highly flexible and adopts a sheet-like structure in solution, which could explain the difficulty in developing potent small-molecule inhibitors. , …”

Section: Synthesis Of Compound 1 Derivatives and Testing For Inhibiti...mentioning

confidence: 99%

“…These strategies assume that uPAR adopts a similar structure in the apo and uPA-bound states, but there is evidence that uPAR is highly flexible and adopts a sheetlike structure in solution, which could explain the difficulty in developing potent small-molecule inhibitors. 23,24 Previously, we reported the discovery of fragment 1 (IPR-2992), which binds to uPAR and inhibits its interaction with uPA. 25 The fragment revealed robust but weak inhibition of uPAR•uPA.…”

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confidence: 99%

Design and Synthesis of Fragment Derivatives with a Unique Inhibition Mechanism of the uPAR·uPA Interaction

Bum‐Erdene

Liu

et al. 2020

ACS Med. Chem. Lett.

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There is substantial interest in the development of small molecules that inhibit the tight and highly challenging protein–protein interaction between the glycophosphatidylinositol (GPI)-anchored cell surface receptor uPAR and the serine protease uPA. While preparing derivatives of a fragment-like compound that previously emerged from a computational screen, we identified compound 5 (IPR-3242), which inhibited binding of uPA to uPAR with submicromolar IC50s. The high inhibition potency prompted us to carry out studies to rule out potential aggregation, lack of stability, reactivity, and nonspecific inhibition. We designed and prepared 16 derivatives to further explore the role of each substituent. Interestingly, the compounds only partially inhibited binding of a fluorescently labeled α-helical peptide that binds to uPAR at the uPAR·uPA interface. Collectively, the results suggest that the compounds bind to uPAR outside of the uPAR·uPA interface, trapping the receptor into a conformation that is not able to bind to uPA. Additional studies will have to be carried out to determine whether this unique inhibition mechanism can occur at the cell surface.

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Crystal structure of the unoccupied murine urokinase‐type plasminogen activator receptor (uPAR) reveals a tightly packed DII–DIII unit

Cited by 4 publications

References 78 publications

Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention

Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention

uPAR: An Essential Factor for Tumor Development

Design and Synthesis of Fragment Derivatives with a Unique Inhibition Mechanism of the uPAR·uPA Interaction

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