The First Intrinsic Tenase Complex Inhibitor with Serine Protease Structure Offers a New Perspective in Anticoagulant Therapy

2018 ◽  
Vol 118 (10) ◽  
pp. 1713-1728 ◽  
Author(s):  
Zorica Latinović ◽  
Adrijana Leonardi ◽  
Lidija Kovačič ◽  
Cho Koh ◽  
Jernej Šribar ◽  
...  
Keyword(s):  
Molecular Mass ◽  
Serine Protease ◽  
Blood Coagulation ◽  
Three Dimensional ◽  
Serine Proteinase ◽  
Medical Application ◽  
Structural Features ◽  
Coagulation System ◽  
Three Dimensional Model ◽  
Excessive Bleeding

AbstractComponents of the intrinsic blood coagulation pathway, among them factor VIIIa (FVIIIa), have been recognized as suitable therapeutic targets to treat venous thromboembolism, pathological process behind two very serious cardiovascular diseases, deep vein thrombosis and pulmonary embolism. Here, we describe a unique glycoprotein from the nose-horned viper (Vipera ammodytes ammodytes [Vaa]) venom, Vaa serine proteinase homolog 1 (VaaSPH-1), structurally a serine protease but without an enzymatic activity and expressing potent anticoagulant action in human blood. We demonstrated that one of its targets in the blood coagulation system is FVIIIa of the intrinsic tenase complex, where it antagonizes the binding of FIXa. Anticoagulants with such characteristics are intensively sought, as they would be much safer for medical application as the contemporary drugs, which frequently induce excessive bleeding and other complications. VaaSPH-1 is unlikely to be orally available for chronic usage as it has molecular mass of 35 kDa. However, it represents a very promising template to design low molecular mass FVIIIa-directed anticoagulant substances, based on structural features of the interaction surface between VaaSPH-1 and FVIIIa. To this end, we constructed a three-dimensional model of VaaSPH-1 bound to FVIIIa. The model exposes the 157–loop and the preceding α-helix as the most appropriate structural elements of VaaSPH-1 to be considered as a guideline to synthesize small FVIIIa-binding molecules, potential new generation of anticoagulants.

scholarly journals Correlation between structure and mass distribution of the nuclear pore complex and of distinct pore complex components.

1990 ◽  
Vol 110 (4) ◽  
pp. 883-894 ◽  
Author(s):  
R Reichelt ◽  
A Holzenburg ◽  
E L Buhle ◽  
M Jarnik ◽  
A Engel ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Nuclear Envelope ◽  
Three Dimensional ◽  
Structural Features ◽  
Nuclear Pore ◽  
Xenopus Laevis Oocyte ◽  
Three Dimensional Model ◽  
Transmission Electron ◽  
Freeze Dried

Nuclear pore complexes (NPCs) prepared from Xenopus laevis oocyte nuclear envelopes were studied in "intact" form (i.e., unexposed to detergent) and after detergent treatment by a combination of conventional transmission electron microscopy (CTEM) and quantitative scanning transmission electron microscopy (STEM). In correlation-averaged CTEM pictures of negatively stained intact NPCs and of distinct NPC components (i.e., "rings," "spoke" complexes, and "plug-spoke" complexes), several fine structural features arranged with octagonal symmetry about a central axis could reproducibly be identified. STEM micrographs of unstained/freeze-dried intact NPCs as well as of their components yielded comparable but less distinct features. Mass determination by STEM revealed the following molecular masses: intact NPC with plug, 124 +/- 11 MD; intact NPC without plug, 112 +/- 11 MD; heavy ring, 32 +/- 5 MD; light ring, 21 +/- 4 MD; plug-spoke complex, 66 +/- 8 MD; and spoke complex, 52 +/- 3 MD. Based on these combined CTEM and STEM data, a three-dimensional model of the NPC exhibiting eightfold centrosymmetry about an axis perpendicular to the plane of the nuclear envelope but asymmetric along this axis is proposed. This structural polarity of the NPC across the nuclear envelope is in accord with its well-documented functional polarity facilitating mediated nucleocytoplasmic exchange of molecules and particles.

Analysis and Research of High Speed Milling of Thin-Walled Bracket Part Based on UG NX

2010 ◽  
Vol 129-131 ◽  
pp. 256-260
Author(s):  
Yi Shu Hao ◽  
Chuang Hai ◽  
Xin Xing Zhu
Keyword(s):  
High Speed ◽  
Three Dimensional ◽  
Structural Features ◽  
Milling Process ◽  
Analysis Method ◽  
Three Dimensional Model ◽  
Machining Processes ◽  
Element Analysis ◽  
High Speed Milling ◽  
Tool Paths

Treating high speed milling theory as the guidance, this paper researched high speed milling process of bracket part based on UG NX. Combined with the structural features of bracket part, three dimensional model is built by UG NX CAD and machining processes are worked out after analysis. UG CAM module was applied to fabricate tool paths. At last, finite element analysis method is introduced to study the processing deformation by UG NX NASTRAN module, based on which measures to restrain processing deformations is advanced and processing sequences are optimized.

Effective inhibition of experimental metastasis and prolongation of survival in mice by a potent factor Xa-specific synthetic serine protease inhibitor with weak anticoagulant activity

2005 ◽  
Vol 94 (11) ◽  
pp. 1084-1093 ◽  
Author(s):  
Ingo Banke ◽  
Matthias Arlt ◽  
Markus Mueller ◽  
Stefan Sperl ◽  
Axel Stemberger ◽  
...  
Keyword(s):  
Serine Protease ◽  
Blood Coagulation ◽  
Anticancer Agents ◽  
Cell Lymphoma ◽  
Malignant Tumors ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Metastatic Potential ◽  
Coagulation System ◽  
Complex Activity

SummaryClinical and experimental evidence suggests that the blood coagulation system is involved in the dissemination of malignant tumors. Consequently, anticoagulant agents have been tested as metastasis suppressors in experimental models. Recently, we have found a close correlation between factor Xa (FXa)-specificity of a series of synthetic serine protease inhibitors and their anti-metastatic potential in a murineT-cell lymphoma metastasis model. Interference of such inhibitors with blood-coagulation may represent a major experimental and clinical obstacle. Here, we test anti-metastatic effects of a recently developed, highly specific 3-amidinophenylalanine-type FXa inhibitor, WX-FX4, with weaker anticoagulant activity when compared to well-established FXa inhibitors, such as DX-9065a, as measured by the activated partial thromboplastin time, prothrombin time, prothrombinase complex activity, and coagulation time. Treatment of mice with WX-FX4 (1.5 mg/kg twice daily) led to significant reduction of experimental liver metastasis of a syngeneic T-cell lymphoma in DBA/2 mice (> 90%), and of experimental lung metastasis of a human fibrosarcoma in CD1 nu/nu mice (> 60%). Due to its relatively low anticoagulant activity, daily treatment over 100 days was possible, leading to significant survival benefits without inducing bleeding anomalities. FXa-inhibitors with highly efficient anti-metastatic potential without coagulationrelated side effects may represent important new tools as anticancer agents.

Models of the Bouguer gravity and geologic structure at Yucca Flat, Nevada

Geophysics ◽  
1988 ◽  
Vol 53 (2) ◽  
pp. 231-244 ◽  
Author(s):  
John F. Ferguson ◽  
Roger N. Felch ◽  
Carlos L. V. Aiken ◽  
John S. Oldow ◽  
Holly Dockery
Keyword(s):  
Structural Information ◽  
Three Dimensional ◽  
Structural Features ◽  
Bouguer Gravity ◽  
Three Dimensional Model ◽  
Geologic History ◽  
The West ◽  
Pass Filter ◽  
Low Pass Filter ◽  
Low Pass

The Bouguer gravity anomaly at Yucca Flat, Nevada, has been modeled by two different techniques: the Cordell‐Henderson and Parker‐Oldenburg methods. The three‐dimensional model has incorporated known density and structural information where possible. These models predict the structural relief on the Cenozoic‐Paleozoic contact to within 150 m or about 15 percent of the actual depth. The three‐dimensional Parker‐Oldenburg method has been found to be efficient in an application involving a large (9000 sample) data base. Numerical stability was ensured by the application of a consistent regularization (a low‐pass filter tuned to suppress the noise‐dominated portion of the data spectrum) of the downward continuation operator. The use of a single regularizing filter for the entire model is not completely satisfactory due to the oversmoothing of shallow regions of the basin. The model is useful in the delineation of the geologic history of the area. Structural features in the model support the hypothesis that regional stress fields rotated significantly during the Tertiary. Major structural elements of the basin are well defined on the Cenozoic‐Paleozoic interface. The principal basin‐bounding fault is the large‐throw Carpetbag fault on the west. This fault was most active during the earliest phases of subsidence. The Yucca fault is seen to be a much smaller feature in the model presented here. The basin is rotated down to the west, with normal hinge faults on the eastern margin.

scholarly journals Calibration of a Three-dimensional slope stability evaluation in Brazilian iron open pit mine

2021 ◽  
Author(s):  
Vidal Félix Navarro Torres ◽  
Rodrigo Dockendorff ◽  
Juan Manuel Girao Sotomayor ◽  
Cristian Castro ◽  
Aristotelina Ferreira da Silva
Keyword(s):  
Three Dimensional ◽  
Structural Features ◽  
Open Pit ◽  
Dimensional Model ◽  
Three Dimensional Model ◽  
Strength Parameters ◽  
Dimensional Section ◽  
The Stability ◽  
Evaluation Techniques

Abstract It has historically been frequent among geotechnical practitioners, that the stability analysis of the slopes of an open pit is performed using a two dimensional section representing the highest and steepest walls within a certain geological setting. However, the literature shows that to predict rupture events in an open pit, a three-dimensional analysis would better represent the actual conditions, as the spatial distribution of the lithology and the structural features play an important role when defining the stability of the slopes. This paper presents the case study of an open it located in Brazil, which experienced instabilities between the years 2001-2019. An evaluation of the behavior of the open pit was performed by calibrating the strength parameters to represent the best documented rupture events. The three-dimensional model was made using the FLAC3D software. The results show that there is a good correlation between the results of the model and the reports of past instabilities. Finally, recommendations are presented for the inter-ramp angles for each lithology based on the calibrated stability analyzes performed. This work seeks to contribute to the knowledge in evaluation techniques for the three-dimensional behavior of open pits.

Pseudoknot Structures in Retroviral and Bacteriophage Messenger RNA: a Family of Structurally Related RNA Pseudoknots

1997 ◽  
Vol 3 (S2) ◽  
pp. 95-96
Author(s):  
D.W. Hoffman ◽  
Z. Du ◽  
J.A. Holland ◽  
M.R. Hansen ◽  
Y. Wang ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Three Dimensional ◽  
Structural Features ◽  
Dimensional Structure ◽  
Three Dimensional Model ◽  
Single Nucleotide ◽  
Rna Pseudoknots ◽  
Gene 32 ◽  
Rna Pseudoknot ◽  
Bacteriophage T2

Nuclear magnetic resonance (NMR) spectroscopy was used to determine the three-dimensional structure of an RNA pseudoknot with a sequence corresponding to the 5' end region of the gene 32 messenger RNA of bacteriophage T2. NMR results show that the pseudoknot contains two coaxial A-form helical stems connected by two loops. One of the loops consists of a single nucleotide, which spans the major groove of the seven base pair helical stem 2. The second loop consists of 7 nucleotides, and spans the minor groove of stem 1. A three-dimensional model of the pseudoknot that is consistent with the NMR data will be presented, and features that are likely to be important for stabilizing the pseudoknot structure will be described.A combination of NMR and phylogenetic methods were used to characterize the structural features of RNA pseudoknots that are associated with frameshift and readthrough sites within the retroviral gag-pro messenger RNA. The majority of the retroviral frameshift and readthrough sites were found to be followed by nucleotide sequences that have the potential to form pseudoknots with structures that are remarkably similar to that of the bacteriophage T2 gene 32 mRNA.

Based on Pro/E High Speed Milling of Thin-Walled Stents of Research

2011 ◽  
Vol 295-297 ◽  
pp. 2487-2491
Author(s):  
Jian Qiang Wang
Keyword(s):  
High Speed ◽  
Three Dimensional ◽  
Structural Features ◽  
Milling Process ◽  
Analysis Method ◽  
Three Dimensional Model ◽  
Machining Processes ◽  
Element Analysis ◽  
High Speed Milling ◽  
Tool Paths

Treating high speed milling theory as the guidance, this paper researched high speed milling process of bracket part based on Pro/E. Combined with the structural features of bracket part, three dimensional model is built by Pro/E and machining processes are worked out after analysis. Pro/E module was applied to fabricate tool paths. At last, finite element analysis method is introduced to study the processing deformation by Pro/E module, based on which measures to restrain processing deformations is advanced and processing sequences are optimized.

Structure of human BPI (bactericidal/permeability-increasing protein) and implications for related proteins

2003 ◽  
Vol 31 (4) ◽  
pp. 791-794 ◽  
Author(s):  
L.J. Beamer
Keyword(s):  
Three Dimensional ◽  
Structural Features ◽  
Secretory Protein ◽  
Sequence Database ◽  
Dimensional Model ◽  
Three Dimensional Model ◽  
X Ray ◽  
Fold Family ◽  
Parotid Secretory Protein ◽  
Related Proteins

Human bactericidal/permeability-increasing protein (BPI) belongs to a family of mammalian lipopolysaccharide-binding and lipid transport proteins. Recent sequence database searches indicate that several other protein families, including the palate, lung and nasal epithelial clone (PLUNC), parotid secretory protein (PSP) and BPI-like proteins, are likely to share the BPI fold, which was determined through X-ray crystallographic studies. As the single representative of its fold family of known structure, the three-dimensional model of BPI suggests structural features that are likely to be conserved across this large and varied group of proteins.

scholarly journals Structure-Function Relationships of Glucansucrase and Fructansucrase Enzymes from Lactic Acid Bacteria

2006 ◽  
Vol 70 (1) ◽  
pp. 157-176 ◽  
Author(s):  
Sacha A. F. T. van Hijum ◽  
Slavko Kralj ◽  
Lukasz K. Ozimek ◽  
Lubbert Dijkhuizen ◽  
Ineke G. H. van Geel-Schutten
Keyword(s):  
Lactic Acid ◽  
Lactic Acid Bacteria ◽  
Molecular Mass ◽  
Catalytic Domain ◽  
Structural Information ◽  
Protein Structures ◽  
Three Dimensional ◽  
Structural Features ◽  
Product Specificity ◽  
Gram Positive Bacteria

SUMMARY Lactic acid bacteria (LAB) employ sucrase-type enzymes to convert sucrose into homopolysaccharides consisting of either glucosyl units (glucans) or fructosyl units (fructans). The enzymes involved are labeled glucansucrases (GS) and fructansucrases (FS), respectively. The available molecular, biochemical, and structural information on sucrase genes and enzymes from various LAB and their fructan and α-glucan products is reviewed. The GS and FS enzymes are both glycoside hydrolase enzymes that act on the same substrate (sucrose) and catalyze (retaining) transglycosylation reactions that result in polysaccharide formation, but they possess completely different protein structures. GS enzymes (family GH70) are large multidomain proteins that occur exclusively in LAB. Their catalytic domain displays clear secondary-structure similarity with α-amylase enzymes (family GH13), with a predicted permuted (β/α)8 barrel structure for which detailed structural and mechanistic information is available. Emphasis now is on identification of residues and regions important for GS enzyme activity and product specificity (synthesis of α-glucans differing in glycosidic linkage type, degree and type of branching, glucan molecular mass, and solubility). FS enzymes (family GH68) occur in both gram-negative and gram-positive bacteria and synthesize β-fructan polymers with either β-(2→6) (inulin) or β-(2→1) (levan) glycosidic bonds. Recently, the first high-resolution three-dimensional structures have become available for FS (levansucrase) proteins, revealing a rare five-bladed β-propeller structure with a deep, negatively charged central pocket. Although these structures have provided detailed mechanistic insights, the structural features in FS enzymes dictating the synthesis of either β-(2→6) or β-(2→1) linkages, degree and type of branching, and fructan molecular mass remain to be identified.

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