Prediction of Molecular Interaction between Platelet Glycoprotein Ibα and von Willebrand Factor using Molecular Dynamics Simulations

Shiozaki, Seiji; Takagi, Shu; Goto, Shinya

doi:10.5551/jat.32458

Cited by 26 publications

(34 citation statements)

References 53 publications

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“…4). The same was supported in prediction of molecular interaction of platelet glycoprotein [39]. This implies that the complex formed with the protein by compound folic acid does not destabilise or denature the protein.…”

Section: Molecular Dynamic Studysupporting

confidence: 59%

Structural dynamics and modeling of curcin protein: docking against pterin derivatives

et al. 2019

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Jatropha species have been widely targeted for its use in oil and biodiesel production. The extraction of oil and biodiesel has been curbed due to the presence of curcin, a toxalbumin that can execute detailed toxic compounds. In silico approaches were undertaken to analyse the inhibition of curcin via pterin inhibitors, which show the structural similarities to ricin inhibitors. The identification of actual residues of predicted active sites, involved in binding with the ligands was accurately confirmed by molecular docking analysis. Among the eleven ligands screened in the present study, particularly, the folic acid showed the maximum docking score, which confirmed their hydrophobic site, hydrogen-bond donor and hydrogen-bond acceptor of folic acid, which could render the optimal biological function through inhibition of curcin.

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Section: Molecular Dynamic Studysupporting

confidence: 59%

Structural dynamics and modeling of curcin protein: docking against pterin derivatives

et al. 2019

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“…The presumption that the A1‐GPIbα complex crystal structure is a real representation of how platelets interact with VWF has become further complexed by concepts of blood rheology, whereby fluid shear flow is thought to promote the β‐hairpin structure outweighing any intrinsic conformational propensities to the contrary. Molecular dynamics studies have also embraced this perspective as true and compute force‐dependent dissociation trajectories based on the structure of the complex to model the forces measured experimentally by single‐molecule methods . Based upon our experimental outcomes, it can be predicted that if fluid shear flow does promote the β‐hairpin conformation, platelet adhesion to VWF would be inhibited, not activated.…”

Section: Discussionmentioning

confidence: 99%

Platelet‐type von Willebrand disease: Local disorder of the platelet GPIbα β‐switch drives high‐affinity binding to von Willebrand factor

Tischer

Machha

Moon‐Tasson

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Mutations in the β‐switch of GPIbα cause gain‐of‐function in the platelet‐type von Willebrand disease. Structures of free and A1‐bound GPIbα suggest that the β‐switch undergoes a conformational change from a coil to a β‐hairpin. Objectives Platelet‐type von Willebrand disease (VWD) mutations have been proposed to stabilize the β‐switch by shifting the equilibrium in favor of the β‐hairpin, a hypothesis predicated on the assumption that the complex crystal structure between A1 and GPIbα is the high‐affinity state. Methods Hydrogen‐deuterium exchange mass spectrometry is employed to test this hypothesis using G233V, M239V, G233V/M239V, W230L, and D235Y disease variants of GPIbα. If true, the expectation is a decrease in hydrogen‐deuterium exchange within the β‐switch as a result of newly formed hydrogen bonds between the β‐strands of the β‐hairpin. Results Hydrogen—exchange is enhanced, indicating that the β‐switch favors the disordered loop conformation. Hydrogen—exchange is corroborated by differential scanning calorimetry, which confirms that these mutations destabilize GPIbα by allowing the β‐switch to dissociate from the leucine‐rich‐repeat (LRR) domain. The stability of GPIbα and its A1 binding affinity, determined by surface plasmon resonance, are correlated to the extent of hydrogen exchange in the β‐switch. Conclusion These studies demonstrate that GPIbα with a disordered loop is binding‐competent and support a mechanism in which local disorder in the β‐switch exposes the LRR—domain of GPIbα enabling high‐affinity interactions with the A1 domain.

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“…VWF is a multimeric glycoprotein that binds platelets at the site of vascular injury and promotes perplatelet–platelet interactions 9) . HMW-VWFMs are particularly important for hemostasis under high shear stress conditions.…”

Section: Introductionmentioning

confidence: 99%

Rapid Restoration of Thrombus Formation and High-Molecular-Weight von Willebrand Factor Multimers in Patients with Severe Aortic Stenosis After Valve Replacement

Yamashita

Yano

Hayakawa

et al. 2016

JAT

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Aim: Patients with severe aortic stenosis (AS) may have bleeding episodes due to the loss of high-molecular-weight (HMW) von Willebrand factor multimers (VWFMs). The absence of HMW-VWFMs and bleeding tendency are usually corrected after aortic valve replacement (AVR). To investigate the process of VWFM recovery and symptoms in patients with severe AS, we analyzed changes in VWF antigen (VWF:Ag), ADAMTS13 activity (ADAMTS13:AC), and platelet thrombus formation under high shear stress conditions.Methods: Nine patients with severe AS undergoing AVR were analyzed.Results: Evident deficiency of HMW-VWFMs was observed in six patients before surgery, which was rapidly restored within 8 days after AVR. Median levels of VWF:Ag before surgery, on postoperative days (PODs) 1, 8, 15, and 22, and one year after AVR were 78.1%, 130%, 224%, 155%, 134%, and 142%, respectively. In contrast, ADAMTS13:AC was 50.5%, 35.5%, 25.5%, 25.1%, 30.3%, and 84.6%, respectively. Preoperative thrombus formation but not surface coverage was significantly lower than that on POD 22, which was considered as normal level in each patient. Compared with preoperative levels, thrombus volume was significantly lower on POD 1, but rapidly increased by POD 8.Conclusion: Bleeding tendency and loss of HMW-VWFMs observed in patients with severe AS before surgery was rapidly corrected after AVR. Instead, patients were in a VWF-predominant state between POD 8 and 22.

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Prediction of Molecular Interaction between Platelet Glycoprotein Ibα and von Willebrand Factor using Molecular Dynamics Simulations

Abstract: Aim: The molecular mechanism of the unique interaction between platelet membrane glycoprotein Ib (GPIb ) and von Willebrand Factor (VWF), necessary for platelet adhesion under high shear stress, is yet to be clarified.

Cited by 26 publications

References 53 publications

Structural dynamics and modeling of curcin protein: docking against pterin derivatives

Structural dynamics and modeling of curcin protein: docking against pterin derivatives

Platelet‐type von Willebrand disease: Local disorder of the platelet GPIbα β‐switch drives high‐affinity binding to von Willebrand factor

Rapid Restoration of Thrombus Formation and High-Molecular-Weight von Willebrand Factor Multimers in Patients with Severe Aortic Stenosis After Valve Replacement

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