Biological activity as an effect of structural changes in aryl N-methylcarbamates

1968 ◽  
Vol 16 (4) ◽  
pp. 605-607 ◽  
Author(s):  
R. P. Miskus ◽  
Melvin. Look ◽  
T. L. Andrews ◽  
R. L. Lyon
Keyword(s):  
Biological Activity ◽  
Structural Changes

scholarly journals Structural control of fibrin bioactivity by mechanical deformation

2020 ◽  
Author(s):  
Sachin Kumar ◽  
Yujen Wang ◽  
Manuel K. Rausch ◽  
Sapun H. Parekh
Keyword(s):  
Biological Activity ◽  
Conformational Changes ◽  
Structural Control ◽  
Structural Changes ◽  
Tensile Deformation ◽  
Mechanical Strain ◽  
Fibrous Protein ◽  
Binding Partners ◽  
Blood Clots ◽  
Β Sheet

AbstractFibrin is a fibrous protein network that entraps blood cells and platelets to form blood clots following vascular injury. As a biomaterial, fibrin acts a biochemical scaffold as well as a viscoelastic patch that resists mechanical insults. The biomechanics and biochemistry of fibrin have been well characterized independently, showing that fibrin is a hierarchical material with numerous binding partners. However, comparatively little is known about how fibrin biomechanics and biochemistry are coupled: how does fibrin deformation influence its biochemistry at the molecular level? In this study, we show how mechanically-induced molecular structural changes in fibrin affect fibrin biochemistry and fibrin-platelet interaction. We found that tensile deformation of fibrin lead to molecular structural transitions of α-helices to β-sheets, which reduced binding of tissue plasminogen activator (tPA), an enzyme that initiates fibrinolysis, at the network and single fiber level. Moreover, binding of tPA and Thioflavin T (ThT), a commonly used β-sheet marker, was primarily mutually exclusive such that tPA bound to native (helical) fibrin whereas ThT bound to strained fibrin. Finally, we demonstrate that conformational changes in fibrin suppressed the biological activity of platelets on mechanically strained fibrin due to attenuated αIIbβ3 integrin binding. Our work shows that mechanical strain regulates fibrin molecular structure and fibrin biological activity in an elegant mechano-chemical feedback loop, which likely influences fibrinolysis and wound healing kinetics.

scholarly journals Molecular-Level Understanding of the Influence of Ions and Water on HMGB1 Adsorption Induced by Surface Hydroxylation of Titanium Implants

2021 ◽  
Author(s):  
Dineli Ranathunga ◽  
Alexandra Arteaga ◽  
Claudia C. Biguetti ◽  
Danieli C. Rodrigues ◽  
Steven O. Nielsen
Keyword(s):  
Biological Activity ◽  
Structural Changes ◽  
High Mobility ◽  
Titanium Implant ◽  
Water Layer ◽  
Titanium Implants ◽  
Surgical Trauma ◽  
Hmgb1 Protein ◽  
Implant Surface ◽  
Surface Hydroxylation

<div><div><div><p>Due to its excellent chemical and mechanical properties, titanium has become the material of choice for orthopedic and dental implants to promote rehabilitation via bone anchorage and osseointegration. Titanium osseointegration is partially related to its capability to form a TiO<sub>2</sub> surface layer and its ability to interact with key endogenous proteins immediately upon implantation, establishing the first bone-biomaterial interface. Surgical trauma caused by implantation results in the release of High Mobility Group Box 1 (HMGB1) protein, which is a prototypic DAMP (Damage Associated Molecular Pattern) with multiple roles in inflammation and tissue healing. To develop different surface strategies that improve the clinical outcome of titanium-based implants by controlling their biological activity, a molecular-scale understanding of HMGB1-surface interactions is desired. Here, we use molecular dynamics (MD) computer simulations to provide direct insight into the HMGB1 interactions and the possible molecular arrangements of HMGB1 on fully hydroxylated and non-hydroxylated rutile (110) TiO<sub>2</sub> surfaces. The results establish that HMGB1 is most likely to be adsorbed directly onto the surface regardless of surface hydroxylation, which is undesirable because it could affect its biological activity by causing structural changes to the protein. The hydroxylated TiO<sub>2</sub> surface shows a greater affinity for HMGB1 than the non-hydroxylated surface. The water layer on the non-hydroxylated TiO<sub>2</sub> surface prevents ions and the protein from directly contacting the surface. However, it was observed that if the ionic strength increases, the total number of ions adsorbed on the two surfaces increases, and the protein’s direct adsorption ability decreases. These findings will help to understand the HMGB1-TiO<sub>2</sub> interactions upon implantation, as well as the development of different surface strategies by introducing ions or ionic materials to the titanium implant surface to modulate its interactions with HMGB1 to preserve biological function.</p></div></div></div>

Structural changes to ribonuclease A and their effects on biological activity

1999 ◽  
Vol 123 (2) ◽  
pp. 103-111 ◽  
Author(s):  
Josef Souček ◽  
Ronald T. Raines ◽  
Monika Haugg ◽  
Sun-Ai Raillard-Yoon ◽  
Steven A. Benner
Keyword(s):  
Biological Activity ◽  
Structural Changes ◽  
Ribonuclease A

Effect of Zn(II) on the Structure and Biological Activity of Natural β-NGF

2004 ◽  
Vol 36 (2) ◽  
pp. 99-104 ◽  
Author(s):  
Guang-Hua Zhao ◽  
Ping Yu ◽  
Xiao-Song Hu ◽  
Lei Zhao
Keyword(s):  
Biological Activity ◽  
Secondary Structure ◽  
Atomic Absorption ◽  
Absorption Spectroscopy ◽  
Atomic Absorption Spectroscopy ◽  
Structural Changes ◽  
Tertiary Structure ◽  
Zinc Ion ◽  
Stopped Flow ◽  
Flameless Atomic Absorption Spectroscopy

Abstract Only β-NGF, the subunit of the 7S NGF complex, exhibits NGF activity, but the function of the zinc ion in native β-NGF has received little attention. Flameless atomic absorption spectroscopy (FAAS) measurements reveal that native β-NGF contains Zn(II) with a Zn(II)/β-NGF stoichiometry of 1:14.6. The presence of Zn(II) in the native molecule results in significant changes of the secondary structure and local tertiary structure around Trp(s) with respect to those of apo β-NGF, as suggested by spectra of fluorescence and circular dichrosim. Stopped-flow studies show that there are at least two steps during the interaction of Zn(II) with the apo form. In comparison with its apo form, the native β-NGF shows a higher ability to trigger the proliferation of TF1 cells and mediate the survival of PC12. Thus it is most likely that the structural changes caused by the presence of Zn(II) directly lead to the increase in the biological activity of β-NGF. All results indicate that Zn(II) in native β-NGF plays an important role in the structure and the biological activity of the protein.

scholarly journals Molecular-Level Understanding of the Influence of Ions and Water on HMGB1 Adsorption Induced by Surface Hydroxylation of Titanium Implants

2021 ◽  
Author(s):  
Dineli Ranathunga ◽  
Alexandra Arteaga ◽  
Claudia C. Biguetti ◽  
Danieli C. Rodrigues ◽  
Steven O. Nielsen
Keyword(s):  
Biological Activity ◽  
Structural Changes ◽  
High Mobility ◽  
Titanium Implant ◽  
Water Layer ◽  
Titanium Implants ◽  
Surgical Trauma ◽  
Hmgb1 Protein ◽  
Implant Surface ◽  
Surface Hydroxylation

<div><div><div><p>Due to its excellent chemical and mechanical properties, titanium has become the material of choice for orthopedic and dental implants to promote rehabilitation via bone anchorage and osseointegration. Titanium osseointegration is partially related to its capability to form a TiO<sub>2</sub> surface layer and its ability to interact with key endogenous proteins immediately upon implantation, establishing the first bone-biomaterial interface. Surgical trauma caused by implantation results in the release of High Mobility Group Box 1 (HMGB1) protein, which is a prototypic DAMP (Damage Associated Molecular Pattern) with multiple roles in inflammation and tissue healing. To develop different surface strategies that improve the clinical outcome of titanium-based implants by controlling their biological activity, a molecular-scale understanding of HMGB1-surface interactions is desired. Here, we use molecular dynamics (MD) computer simulations to provide direct insight into the HMGB1 interactions and the possible molecular arrangements of HMGB1 on fully hydroxylated and non-hydroxylated rutile (110) TiO<sub>2</sub> surfaces. The results establish that HMGB1 is most likely to be adsorbed directly onto the surface regardless of surface hydroxylation, which is undesirable because it could affect its biological activity by causing structural changes to the protein. The hydroxylated TiO<sub>2</sub> surface shows a greater affinity for HMGB1 than the non-hydroxylated surface. The water layer on the non-hydroxylated TiO<sub>2</sub> surface prevents ions and the protein from directly contacting the surface. However, it was observed that if the ionic strength increases, the total number of ions adsorbed on the two surfaces increases, and the protein’s direct adsorption ability decreases. These findings will help to understand the HMGB1-TiO<sub>2</sub> interactions upon implantation, as well as the development of different surface strategies by introducing ions or ionic materials to the titanium implant surface to modulate its interactions with HMGB1 to preserve biological function.</p></div></div></div>

scholarly journals Vitamins D: Relationship between Structure and Biological Activity

2018 ◽  
Vol 19 (7) ◽  
pp. 2119 ◽  
Author(s):  
Andrzej Kutner ◽  
Geoffrey Brown
Keyword(s):  
Vitamin D ◽  
Biological Activity ◽  
Vitamin D Receptor ◽  
Structural Changes ◽  
Cell Types ◽  
Dihydroxyvitamin D3 ◽  
Single Receptor ◽  
Intracellular Signals ◽  
Information Studies

The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D3, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D3 is important to decision-making by cells, driving many cell types to growth arrest, differentiate and undergo apoptosis. 1α,25-Dihydroxyvitamin D3 regulates gene transcription by binding to a single known receptor, the vitamin D receptor. Rapid intracellular signals are also elicited in vitro by 1α,25-dihydroxyvitamin D3 that are independent of transcription. There are many aspects of the multiple actions of 1α,25-dihydroxyvitamin D3 that we do not fully understand. These include how a single receptor and provoked rapid events relate to the different actions of 1α,25-dihydroxyvitamin D3, its calcemic action per se, and whether a large number of genes are activated directly, via the vitamin D receptor, or indirectly. A strategy to resolving these issues has been to generate synthetic analogues of 1α,25-dihydroxyvitamin D3: Some of these separate the anti-proliferative and calcemic actions of the parent hormone. Crystallography is important to understanding how differences between 1α,25-dihydroxyvitamin D3- and analogue-provoked structural changes to the vitamin D receptor may underlie their different activity profiles. Current crystallographic resolution has not revealed such information. Studies of our new analogues have revealed the importance of the A-ring adopting the chair β-conformation upon interaction with the vitamin D receptor to receptor-affinity and biological activity. Vitamin D analogues are useful probes to providing a better understanding of the physiology of vitamin D.

scholarly journals THE BIOLOGICAL ACTIVITY OF SOLUBLE ANTIGEN-ANTIBODY COMPLEXES

1959 ◽  
Vol 109 (2) ◽  
pp. 127-143 ◽  
Author(s):  
Kimishige Ishizaka ◽  
Teruko Ishizaka ◽  
Dan H. Campbell
Keyword(s):  
Biological Activity ◽  
Guinea Pigs ◽  
Structural Changes ◽  
Soluble Antigen ◽  
Skin Reactions ◽  
Antibody Molecule ◽  
Antigen Antibody ◽  
Mechanism Of The Reaction

Soluble BSA-anti-BSA complexes, formed in antigen excess, give immediate skin reactions in normal guinea pigs. The mechanism of the reaction is not that of passive or reversed passive anaphylaxis. The complex itself is toxic. Skin activity of the complex depends on its composition. It has become obvious that the complex composed of two antigen molecules and one antibody molecule, (Ag2Ab), does not have the activity, whereas, Ag3Ab2 and more complicated complexes do. The role of complement as well as speculation on the structural changes of antibody-antigen complexes is presented.

scholarly journals THE FIXATION OF COMPLEMENT AND THE ACTIVATED FIRST COMPONENT (C1) OF COMPLEMENT BY COMPLEXES FORMED BETWEEN ANTIBODY AND DIVALENT HAPTEN

1970 ◽  
Vol 131 (4) ◽  
pp. 783-802 ◽  
Author(s):  
N. E. Hyslop ◽  
R. R. Dourmashkin ◽  
N. M. Green ◽  
R. R. Porter
Keyword(s):  
Biological Activity ◽  
Structural Changes ◽  
Complement Fixation ◽  
Gel Filtration ◽  
Caproic Acid ◽  
Soluble Antigen ◽  
Cooperative Effects ◽  
Immunoglobulin Molecule ◽  
The Individual ◽  
Antigen Antibody

Hapten-antibody complexes prepared at equivalence with the bivalent hapten bis-DNP-octamethylene-diamine and purified rabbit anti-DNP antibody were fractionated by Sepharose gel-filtration and the fractions examined by electron microscopy. Individual fractions were tested for whole-complement fixation and C1 fixation. Dimer forms did not show this type of biological activity, while fractions containing tetramers and larger polymers exhibited both C and C1 fixation, which could be inhibited by prior exposure of the complexes to the univalent hapten epsilon-DNP-caproic acid. The dose-response result indicated that the C-fixation observed was not due to interpolymeric cooperative effects. It was concluded that in the generation of biological activity by soluble antigen-antibody complexes made with complement-fixing antibody, quaternary structural changes following specific combination with antigen may be as important as any tertiary structural alterations that occur in the individual immunoglobulin molecule.

scholarly journals Identifying new topoisomerase II poison scaffolds by combining publicly available toxicity data and 2D/3D-based virtual screening

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Lovrics ◽  
Veronika F. S. Pape ◽  
Dániel Szisz ◽  
Adrián Kalászi ◽  
Petra Heffeter ◽  
...  
Keyword(s):  
Biological Activity ◽  
Topoisomerase Ii ◽  
Structural Changes ◽  
Biological Activities ◽  
Molecular Descriptor ◽  
Tumor Cell Line ◽  
Ring Closure ◽  
Scaffold Hopping ◽  
2D And 3D

Abstract Molecular descriptor (2D) and three dimensional (3D) shape based similarity methods are widely used in ligand based virtual drug design. In the present study pairwise structure comparisons among a set of 4858 DTP compounds tested in the NCI60 tumor cell line anticancer drug screen were computed using chemical hashed fingerprints and 3D molecule shapes to calculate 2D and 3D similarities, respectively. Additionally, pairwise biological activity similarities were calculated by correlating the 60 element vectors of pGI50 values corresponding to the cytotoxicity of the compounds across the NCI60 panel. Subsequently, we compared the power of 2D and 3D structural similarity metrics to predict the toxicity pattern of compounds. We found that while the positive predictive value and sensitivity of 3D and molecular descriptor based approaches to predict biological activity are similar, a subset of molecule pairs yielded contradictory results. By simultaneously requiring similarity of biological activities and 3D shapes, and dissimilarity of molecular descriptor based comparisons, we identify pairs of scaffold hopping candidates displaying characteristic core structural changes such as heteroatom/heterocycle change and ring closure. Attempts to discover scaffold hopping candidates of mitoxantrone recovered known Topoisomerase II (Top2) inhibitors, and also predicted new, previously unknown chemotypes possessing in vitro Top2 inhibitory activity.

Moulting Hormones. LIII. the Synthesis and Biological Activity of Some Ecdysone Analogues

1981 ◽  
Vol 34 (12) ◽  
pp. 2607 ◽  
Author(s):  
M Galbraith ◽  
DS Horn ◽  
B Kelly ◽  
J Kinnear ◽  
M Martin ◽  
...  
Keyword(s):  
Biological Activity ◽  
Hydroxy Group ◽  
Structural Changes ◽  
Mosquito Larvae ◽  
Moulting Hormones

A number of ecdysone analogues were prepared to study the effect of structural changes on biological activity. It was found that analogues with the 5α-configuration or a 3,5-cyclo structure were inactive, that a 3β-hydroxy group enhances activity but is not essential for activity, and that 3β-substituents decrease activity as follows: OMe (60%), OAc (25%) and OEt (10%). The keto diol (3), keto alcohol (9) and amide (36) were found to be highly toxic to mosquito larvae.

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