First Structural Model of Full-Length Human Tissue-Plasminogen Activator: A SAXS Data-Based Modeling Study

Rathore, Yogendra Singh; Rehan, Mohammad; Pandey, Kalpana; Sahni, Girish; Ashish, .

doi:10.1021/jp207243n

Cited by 24 publications

(37 citation statements)

References 36 publications

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“…In experiments that inject a 5-nM bolus of tPA, there are only 3 tPA molecules per cubic micron in the clot; a physiological concentration of tPA (70 pM) amounts to 0.04 molecules/ μ m 3 (Supplement). For context, the length of a tPA molecule in solution is about 10 nm 24 . Assuming the shape of tPA to be spherical (to simplify calculations), the volume of a single tPA molecule is 5.24 × 10 −7 μ m 3 .…”

Section: Resultsmentioning

confidence: 99%

Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments

Bannish

Chernysh

Keener

et al. 2017

Sci Rep

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Despite the common use of thrombolytic drugs, especially in stroke treatment, there are many conflicting studies on factors affecting fibrinolysis. Because of the complexity of the fibrinolytic system, mathematical models closely tied with experiments can be used to understand relationships within the system. When tPA is introduced at the clot or thrombus edge, lysis proceeds as a front. We developed a multiscale model of fibrinolysis that includes the main chemical reactions: the microscale model represents a single fiber cross-section; the macroscale model represents a three-dimensional fibrin clot. The model successfully simulates the spatial and temporal locations of all components and elucidates how lysis rates are determined by the interplay between the number of tPA molecules in the system and clot structure. We used the model to identify kinetic conditions necessary for fibrinolysis to proceed as a front. We found that plasmin regulates the local concentration of tPA through forced unbinding via degradation of fibrin and tPA release. The mechanism of action of tPA is affected by the number of molecules present with respect to fibrin fibers. The physical mechanism of plasmin action (crawling) and avoidance of inhibition is defined. Many of these new findings have significant implications for thrombolytic treatment.

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Section: Resultsmentioning

confidence: 99%

Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments

Bannish

Chernysh

Keener

et al. 2017

Sci Rep

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“…Although our study highlights the importance of including glycans in the SAXS modeling of glycosylated proteins, surprisingly only a handful of studies have adopted similar approaches. For instance, N-linked glycans can be added to the protein using the GlyProt server (Kajander et al, 2011;Rathore et al, 2012), they can be modeled as flexible residues using MODELER (Guttman et al, 2012), or they can be added as movable rigid bodies in SASREF (Alt et al, 2012; Zeev-Ben-Mordehai et al, 2009), although this approach is limited by the number of allowable rigid bodies. Our method allows effective modeling of glycans in glycosylated proteins against SAXS data by combining SASREF-based rigid-body modeling of starting structures, adding missing gaps/loops, and performing subsequent energy minimization runs to obtain stereochemically sound models.…”

Section: Structure Of the Complete Extracellular Assembly Of The Il-3mentioning

confidence: 99%

Human IL-34 and CSF-1 Establish Structurally Similar Extracellular Assemblies with Their Common Hematopoietic Receptor

et al. 2013

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The discovery that hematopoietic human colony stimulating factor-1 receptor (CSF-1R) can be activated by two distinct cognate cytokines, colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34), created puzzling scenarios for the two possible signaling complexes. We here employ a hybrid structural approach based on small-angle X-ray scattering (SAXS) and negative-stain EM to reveal that bivalent binding of human IL-34 to CSF-1R leads to an extracellular assembly hallmarked by striking similarities to the CSF-1:CSF-1R complex, including homotypic receptor-receptor interactions. Thus, IL-34 and CSF-1 have evolved to exploit the geometric requirements of CSF-1R activation. Our models include N-linked oligomannose glycans derived from a systematic approach resulting in the accurate fitting of glycosylated models to the SAXS data. We further show that the C-terminal region of IL-34 is heavily glycosylated and that it can be proteolytically cleaved from the IL-34:hCSF-1R complex, providing insights into its role in the functional nonredundancy of IL-34 and CSF-1.

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“…6Theoretical model of the tertiary structure of tissue plasminogen activator. The visualization is based on the model kindly provided by Ashish and coworkers [78]. T-PA is composed of five domains: finger F (green), epidermal growth factor EGF (purple), kringle K1 (orange), kringle K2 (red), and protease P (blue).…”

Section: Tissue Plasminogen Activatormentioning

confidence: 99%

Structural Biology and Protein Engineering of Thrombolytics

Mičan

Toul

Bednář

et al. 2019

Computational and Structural Biotechnology Journal

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Myocardial infarction and ischemic stroke are the most frequent causes of death or disability worldwide. Due to their ability to dissolve blood clots, the thrombolytics are frequently used for their treatment. Improving the effectiveness of thrombolytics for clinical uses is of great interest. The knowledge of the multiple roles of the endogenous thrombolytics and the fibrinolytic system grows continuously. The effects of thrombolytics on the alteration of the nervous system and the regulation of the cell migration offer promising novel uses for treating neurodegenerative disorders or targeting cancer metastasis. However, secondary activities of thrombolytics may lead to life-threatening side-effects such as intracranial bleeding and neurotoxicity. Here we provide a structural biology perspective on various thrombolytic enzymes and their key properties: (i) effectiveness of clot lysis, (ii) affinity and specificity towards fibrin, (iii) biological half-life, (iv) mechanisms of activation/inhibition, and (v) risks of side effects. This information needs to be carefully considered while establishing protein engineering strategies aiming at the development of novel thrombolytics. Current trends and perspectives are discussed, including the screening for novel enzymes and small molecules, the enhancement of fibrin specificity by protein engineering, the suppression of interactions with native receptors, liposomal encapsulation and targeted release, the application of adjuvants, and the development of improved production systems.

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First Structural Model of Full-Length Human Tissue-Plasminogen Activator: A SAXS Data-Based Modeling Study

Cited by 24 publications

References 36 publications

Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments

Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments

Human IL-34 and CSF-1 Establish Structurally Similar Extracellular Assemblies with Their Common Hematopoietic Receptor

Structural Biology and Protein Engineering of Thrombolytics

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