keyword
https://read.qxmd.com/read/38533078/revisiting-the-effect-of-cholesteryl-sulfate-on-clotting-and-fibrinolysis-inhibition-of-human-thrombin-and-other-human-blood-proteases
#1
JOURNAL ARTICLE
Rami A Al-Horani
Cholesteryl sulfate (CS) was quantitatively synthesized by microwave-assisted sulfonation of cholesterol followed by sodium exchange chromatography. In vitro effects of CS on human thrombin and other serine proteases of the coagulation and fibrinolysis processes were investigated using a series of biochemical and biophysical techniques. CS was found to inhibit thrombin with an IC 50 value of 140.8 ± 21.8 μM at pH 7.4 and 25 ○ C. Michaelis-Menten kinetics indicated that thrombin inhibition by CS is non-competitive (allosteric) in nature...
March 30, 2024: Heliyon
https://read.qxmd.com/read/38521329/a-common-protein-c-inhibitor-exosite-partially-controls-the-heparin-induced-activation-and-inhibition-of-serine-proteases
#2
JOURNAL ARTICLE
Urfi Siddiqui, Abdul Burhan Khan, Tahif Ahmad, Ahmed Abdur Rehman, Mohamad Aman Jairajpuri
Protein C inhibitor (PCI) maintains hemostasis by inhibiting both procoagulant and anticoagulant serine proteases, and plays important roles in coagulation, fibrinolysis, reproduction, and anti-angiogenesis. The reactive site loop of PCI traps and irreversibly inhibits the proteases like APC (activating protein C), thrombin (FIIa) and factor Xa (FXa). Previous studies on antithrombin (ATIII) had identified Tyr253 and Glu255 as functional exosites that interact and aid in the inhibition of factor IXa and FXa...
March 21, 2024: International Journal of Biological Macromolecules
https://read.qxmd.com/read/38497531/caspase-1-activates-gasdermin-a-in-non-mammals
#3
JOURNAL ARTICLE
Zachary Paul Billman, Stephen Bela Kovacs, Bo Wei, Kidong Kang, Ousmane H Cissé, Edward A Miao
Gasdermins oligomerize to form pores in the cell membrane, causing regulated lytic cell death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase and granzyme proteases cleave the linker regions of and activate GSDMB, C, D, and E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis of the gasdermin family. A gene duplication of GSDMA in the common ancestor of caecilian amphibians, reptiles, and birds gave rise to GSDMA-D in mammals...
March 18, 2024: ELife
https://read.qxmd.com/read/38474611/novel-scaffold-agonists-of-the-%C3%AE-2a-adrenergic-receptor-identified-via-ensemble-based-strategy
#4
JOURNAL ARTICLE
Shiyang Sun, Pengyun Li, Jiaqi Wang, Dongsheng Zhao, Tingting Yang, Peilan Zhou, Ruibin Su, Zhibing Zheng, Song Li
The α2A adrenergic receptor (α2A -AR) serves as a critical molecular target for sedatives and analgesics. However, α2A -AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold α2A -AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential α2A -AR agonists with novel scaffold...
February 29, 2024: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/38382740/a-specific-fluorescence-resonance-energy-quenching-based-biosensor-for-measuring-thrombin-activity-in-whole-blood
#5
JOURNAL ARTICLE
Ying Dai, Colin A Kretz, Paul Y Kim, Peter L Gross
BACKGROUND: At sites of vessel injury, thrombin acts as the central mediator of coagulation by catalyzing fibrin clot formation and platelet activation. Thrombin generation is most frequently measured in plasma samples using small molecule substrates, however these have low specificity for thrombin and limited utility in whole blood. Plasma assays are limited because they ignore the hemostatic contributions of blood cells, require anticoagulation and the addition of supraphysiological concentrations of calcium...
February 19, 2024: Journal of Thrombosis and Haemostasis: JTH
https://read.qxmd.com/read/38372634/molecular-interactions-required-for-activation-of-complement-component-c2-include-exosites-located-on-the-serine-protease-domain-of-c1s-and-mannose-binding-lectin-associated-protease-2
#6
JOURNAL ARTICLE
Lilian Hor, Jing Pan, Robert N Pike, Lakshmi C Wijeyewickrema
The activation of the CP/LP C3 proconvertase complex is a key event in complement activation and involves cleavage of C4 and C2 by the C1s protease (classical pathway) or the mannose-binding lectin-associated serine protease (MASP)-2 (lectin pathway). Efficient cleavage of C4 by C1s and MASP-2 involves exosites on the complement control protein and serine protease (SP) domains of the proteases. The complement control protein domain exosite is not involved in cleavage of C2 by the proteases, but the role of an anion-binding exosite (ABE) on the SP domains of the proteases has (to our knowledge) never been investigated...
February 19, 2024: Journal of Immunology
https://read.qxmd.com/read/38318153/site-directed-mutagenesis-of-tissue-factor-pathway-inhibitor-binding-exosite-d60a-on-factor-vii-results-in-a-new-factor-vii-variant-with-lower-coagulant-activity
#7
JOURNAL ARTICLE
Karnsasin Seanoon, Vorawat Kitiyanant, Panwajee Payongsri, Nongnuch Sirachainan, Pantep Angchaisuksiri, Ampaiwan Chuansumrit, Suradej Hongeng, Pansakorn Tanratana
BACKGROUND: Recombinant factor (F)VIIa (rFVIIa) has been approved by the US Food and Drug Administration for the treatment of hemophilia A and B with inhibitors and congenital FVII deficiency. Moreover, the investigational uses of rFVIIa are becoming of interest since it can be used to treat various clinical bleeding conditions. However, there is evidence showing that rFVIIa is a potent procoagulant agent that potentially leads to an increased risk of thrombotic complications. OBJECTIVES: To design a new rFVII with lower coagulant activity that could potentially be used as an alternative hemostatic agent aiming to minimize the risk of thrombogenicity...
January 2024: Research and Practice in Thrombosis and Haemostasis
https://read.qxmd.com/read/38256920/an-adam10-exosite-inhibitor-is-efficacious-in-an-in-vivo-collagen-induced-arthritis-model
#8
JOURNAL ARTICLE
Juan Diez, Michael E Selsted, Thomas D Bannister, Dmitriy Minond
Rheumatoid arthritis is a systemic autoimmune inflammatory disease that affects millions of people worldwide. There are multiple disease-modifying anti-rheumatic drugs available; however, many patients do not respond to any treatment. A disintegrin and metalloproteinase 10 has been suggested as a potential new target for RA due to its role in the release of multiple pro- and anti-inflammatory factors from cell surfaces. In the present study, we determined the pharmacokinetic parameters and in vivo efficacy of a compound CID3117694 from a novel class of non-zinc-binding inhibitors...
January 9, 2024: Pharmaceuticals
https://read.qxmd.com/read/38110403/a-darpin-promotes-faster-onset-of-botulinum-neurotoxin-a1-action
#9
JOURNAL ARTICLE
Oneda Leka, Yufan Wu, Giulia Zanetti, Sven Furler, Thomas Reinberg, Joana Marinho, Jonas V Schaefer, Andreas Plückthun, Xiaodan Li, Marco Pirazzini, Richard A Kammerer
In this study, we characterize Designed Ankyrin Repeat Proteins (DARPins) as investigative tools to probe botulinum neurotoxin A1 (BoNT/A1) structure and function. We identify DARPin-F5 that completely blocks SNAP25 substrate cleavage by BoNT/A1 in vitro. X-ray crystallography reveals that DARPin-F5 inhibits BoNT/A1 activity by interacting with a substrate-binding region between the α- and β-exosite. This DARPin does not block substrate cleavage of BoNT/A3, indicating that DARPin-F5 is a subtype-specific inhibitor...
December 18, 2023: Nature Communications
https://read.qxmd.com/read/38089466/nonallosteric-activation-of-posttranslational-modification-enzymes-by-active-site-directed-inhibitors
#10
JOURNAL ARTICLE
Alessandro Pesaresi
Activation-by-inhibition is a biochemical paradox seldom observed in exosite enzymes, wherein active site-bound inhibitors unexpectedly lead to enzyme activation. This intriguing phenomenon occurs at low, undersaturating substrate concentrations, posing a significant challenge in drug discovery, especially when targeting enzymes such as protein kinases, proteases, and other posttranslational modification enzymes. These enzymes often rely on accessory recognition sites known as exosites, which contribute to complex substrate binding mechanisms and unique kinetic behaviors...
December 2024: Computational and Structural Biotechnology Journal
https://read.qxmd.com/read/38089051/flavonol-and-a-type-procyanidin-rich-extracts-of-prunus-spinosa-l-flower-exhibit-anticoagulant-activity-through-direct-thrombin-inhibition-but-do-not-affect-platelet-aggregation-in-vitro
#11
JOURNAL ARTICLE
Anna Marchelak, Joanna Kolodziejczyk-Czepas, Michał B Ponczek, Oleksandra Liudvytska, Magdalena Markowicz-Piasecka, Beata Bielska, Katarzyna Miłowska, Monika A Olszewska
Background: Blackthorn flower ( Prunus spinosa L.) is a traditional herbal remedy recommended for treating cardiovascular diseases (CVDs). Aim: This in vitro study investigates the effects of flavonol and A-type procyanidin-rich blackthorn flower extracts on the hemostatic system, including the blood plasma coagulation cascade and platelet aggregation. Methods: Six distinct extracts, characterized through various techniques, including LC-MS/MS, were assessed at in vivo -relevant levels (1-50 μg/mL) for their antithrombotic activity...
2023: Frontiers in Pharmacology
https://read.qxmd.com/read/38069440/regulation-of-peptidase-activity-beyond-the-active-site-in-human-health-and-disease
#12
REVIEW
Ana Obaha, Marko Novinec
This comprehensive review addresses the intricate and multifaceted regulation of peptidase activity in human health and disease, providing a comprehensive investigation that extends well beyond the boundaries of the active site. Our review focuses on multiple mechanisms and highlights the important role of exosites, allosteric sites, and processes involved in zymogen activation. These mechanisms play a central role in shaping the complex world of peptidase function and are promising potential targets for the development of innovative drugs and therapeutic interventions...
December 4, 2023: International Journal of Molecular Sciences
https://read.qxmd.com/read/38055188/effect-of-sulfotyrosine%C3%A2-and-negatively-charged-amino-acid-of-leech-derived-peptides-on-binding-and-inhibitory-activity-against-thrombin
#13
JOURNAL ARTICLE
Tzu-Yin Chen, Eileen Shyur, Tzu-Hsuan Ma, Lakshmi Wijeyewickrema, Sheng-Wei Lin, Mu-Rong Kao, Pi-Hui Liang, Jiun-Jie Shie, Er-Yuan Chuang, Jing-Ping Liou, Yves Sy Hsieh
Hirudins, natural sulfo(glyco)proteins, are clinical anticoagulants that directly inhibit thrombin, a key coagulation factor. Their potent thrombin inhibition primarily results from antagonistic interactions with both the catalytic and non-catalytic sites of thrombin. Hirudins often feature sulfate moieties on Tyr residues in their anionic C-terminus region, enabling strong interactions with thrombin exosite-I and effectively blocking its engagement with fibrinogen. Although sulfotyrosines have been identified in various hirudin variants, the precise relationship between sulfotyrosine and the number of negatively charged amino acids within the anionic-rich C-terminus peptide domain for the binding of thrombin has remained elusive...
December 6, 2023: Chembiochem: a European Journal of Chemical Biology
https://read.qxmd.com/read/38040684/author-correction-discovery-of-an-exosite-on-the-socs2-sh2-domain-that-enhances-sh2-binding-to-phosphorylated-ligands
#14
Edmond M Linossi, Kunlun Li, Gianluca Veggiani, Cyrus Tan, Farhad Dehkhoda, Colin Hockings, Dale J Calleja, Narelle Keating, Rebecca Feltham, Andrew J Brooks, Shawn S Li, Sachdev S Sidhu, Jeffrey J Babon, Nadia J Kershaw, Sandra E Nicholson
No abstract text is available yet for this article.
December 1, 2023: Nature Communications
https://read.qxmd.com/read/37996063/anixodes-persulcatusinhibitor-of-plasmin-and-thrombin-hinders-keratinocyte-migration-blood-coagulation-and-endothelial-permeability
#15
JOURNAL ARTICLE
Markus Berger, Sheila Rosa da Mata, Nicolle Masseroni Pizzolatti, Luís Fernando Parizi, Satoru Konnai, Itabajara da Silva Vaz, Adriana Seixas, Lucas Tirloni
The skin is the first host tissue that the tick mouthparts, tick saliva, and a tick-borne pathogen contact during feeding. Tick salivary glands have evolved a complex and sophisticated pharmacological arsenal, consisting of bioactive molecules, to assist blood feeding and pathogen transmission. In this work, persulcatin, a multifunctional molecule that targets keratinocyte function and hemostasis, was identified from Ixodes persulcatus female ticks. The recombinant persulcatin was expressed and purified and is a 25 kDa acidic protein with two Kunitz-type domains...
November 21, 2023: Journal of Investigative Dermatology
https://read.qxmd.com/read/37993714/recognition-and-maturation-of-il-18-by-caspase-4-noncanonical-inflammasome
#16
JOURNAL ARTICLE
Xuyan Shi, Qichao Sun, Yanjie Hou, Huan Zeng, Yong Cao, Mengqiu Dong, Jingjin Ding, Feng Shao
The canonical (caspase-1) and noncanonical (comprising caspases 4, 5 and 11; hereafter, caspase-4/5/11) inflammasomes both cleave gasdermin D (GSDMD) to induce pyroptosis1,2 . Whereas caspase-1 processes IL-1β and IL-18 for maturation3-6 , no cytokine target has been firmly established for lipopolysaccharide-activated caspase-4/5/117-9 . Here we show that activated human caspase-4, but not mouse caspase-11, directly and efficiently processes IL-18 in vitro and during bacterial infections. Caspase-4 cleaves the same tetrapeptide site in pro-IL-18 as caspase-1...
November 22, 2023: Nature
https://read.qxmd.com/read/37993712/structural-insights-into-cytokine-cleavage-by-inflammatory-caspase-4
#17
JOURNAL ARTICLE
Pascal Devant, Ying Dong, Julian Mintseris, Weiyi Ma, Steven P Gygi, Hao Wu, Jonathan C Kagan
Inflammatory caspases are key enzymes in mammalian innate immunity that control the processing and release of interleukin-1 (IL-1)-family cytokines1,2 . Despite the biological importance, the structural basis for inflammatory caspase-mediated cytokine processing has remained unclear. To date, catalytic cleavage of IL-1-family members, including pro-IL-1β and pro-IL-18, has been attributed primarily to caspase-1 activities within canonical inflammasomes3 . Here we demonstrate that the lipopolysaccharide receptor caspase-4 from humans and other mammalian species (except rodents) can cleave pro-IL-18 with an efficiency similar to pro-IL-1β and pro-IL-18 cleavage by the prototypical IL-1-converting enzyme caspase-1...
November 22, 2023: Nature
https://read.qxmd.com/read/37987010/caspase-1-activates-gasdermin-a-in-all-non-mammals
#18
Zachary P Billman, Stephen B Kovacs, Bo Wei, Kidong Kang, Ousmane H Cissé, Edward A Miao
UNLABELLED: Gasdermins oligomerize to form pores in the cell membrane, causing programmed lytic cell death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase and granzyme proteases cleave the linker regions of and activate GSDMB, C, D, and E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis of the gasdermin family and focus on the first gene amplification event that gave rise to mammal GSDMA-D by studying GSDMA in non-mammal species including amphibians, reptiles, and birds...
September 28, 2023: bioRxiv
https://read.qxmd.com/read/37924304/from-haemadin-to-haemanorm-synthesis-and-characterization-of-full-length-haemadin-from-the-leech-haemadipsa-sylvestris-and-of-a-novel-bivalent-highly-potent-thrombin-inhibitor-haemanorm
#19
JOURNAL ARTICLE
Laura Acquasaliente, Andrea Pierangelini, Anna Pagotto, Nicola Pozzi, Vincenzo De Filippis
Hirudin from Hirudo medicinalis is a bivalent α-Thrombin (αT) inhibitor, targeting the enzyme active site and exosite-I, and is currently used in anticoagulant therapy along with its simplified analogue hirulog. Haemadin, a small protein (57 amino acids) isolated from the land-living leech Haemadipsa sylvestris, selectively inhibits αT with a potency identical to that of recombinant hirudin (KI  = 0.2 pM), with which it shares a common disulphide topology and overall fold. At variance with hirudin, haemadin targets exosite-II and therefore (besides the free protease) it also blocks thrombomodulin-bound αT without inhibiting the active intermediate meizothrombin, thus offering potential advantages over hirudin...
November 4, 2023: Protein Science
https://read.qxmd.com/read/37828045/molecular-mechanism-of-decision-making-in-glycosaminoglycan-biosynthesis
#20
JOURNAL ARTICLE
Douglas Sammon, Anja Krueger, Marta Busse-Wicher, Rhodri Marc Morgan, Stuart M Haslam, Benjamin Schumann, David C Briggs, Erhard Hohenester
Two major glycosaminoglycan types, heparan sulfate (HS) and chondroitin sulfate (CS), control many aspects of development and physiology in a type-specific manner. HS and CS are attached to core proteins via a common linker tetrasaccharide, but differ in their polymer backbones. How core proteins are specifically modified with HS or CS has been an enduring mystery. By reconstituting glycosaminoglycan biosynthesis in vitro, we establish that the CS-initiating N-acetylgalactosaminyltransferase CSGALNACT2 modifies all glycopeptide substrates equally, whereas the HS-initiating N-acetylglucosaminyltransferase EXTL3 is selective...
October 13, 2023: Nature Communications
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