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https://www.readbyqxmd.com/read/28445754/probing-the-dynamics-of-clot-bound-thrombin-at-venous-shear-rates
#1
Laura M Haynes, Thomas Orfeo, Kenneth G Mann, Stephen J Everse, Kathleen E Brummel-Ziedins
In closed system models of fibrin formation, exosite-mediated thrombin binding to fibrin contributes to clot stability and is resistant to inhibition by antithrombin/heparin while still susceptible to small, active-site inhibitors. Each molecule of fibrin can bind ∼1.6 thrombin molecules at low-affinity binding sites (Kd = 2.8 μM) and ∼0.3 molecules of thrombin at high-affinity binding sites (Kd = 0.15 μM). The goal of this study is to assess the stability of fibrin-bound thrombin under venous flow conditions and to determine both its accessibility and susceptibility to inhibition...
April 25, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28442704/discovery-of-an-enzyme-and-substrate-selective-inhibitor-of-adam10-using-an-exosite-binding-glycosylated-substrate
#2
Franck Madoux, Daniela Dreymuller, Jean-Phillipe Pettiloud, Radleigh Santos, Christoph Becker-Pauly, Andreas Ludwig, Gregg B Fields, Thomas Bannister, Timothy P Spicer, Mare Cudic, Louis D Scampavia, Dmitriy Minond
ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recent years, there has been a shift from active site to secondary substrate binding site (exosite) inhibitor discovery in order to identify non-zinc-binding molecules. In the present work a glycosylated, exosite-binding substrate of ADAM10 and ADAM17 was utilized to screen 370,276 compounds from the MLPCN collection...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28363953/avathrin-a-novel-thrombin-inhibitor-derived-from-a-multi-copy-precursor-in-the-salivary-glands-of-the-ixodid-tick-amblyomma-variegatum
#3
Janaki Krishnamoorthy Iyer, Cho Yeow Koh, Maria Kazimirova, Ladislav Roller, Chacko Jobichen, Kunchithapadam Swaminathan, Jun Mizuguchi, Sadaaki Iwanaga, Patricia A Nuttall, Mark Y Chan, R Manjunatha Kini
Tick saliva is a rich source of antihemostatic compounds. We amplified a cDNA from the salivary glands of the tropical bont tick (Amblyomma variegatum) using primers based on the variegin sequence, which we previously identified as a novel thrombin inhibitor from the same tick species. The transcript encodes a precursor protein comprising a signal peptide and 5 repeats of variegin-like sequences that could be processed into multiple short peptides. These peptides share 31 to 34% identity with variegin. Here, we structurally and functionally characterized one of these peptides named "avathrin...
March 31, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28299739/mapping-the-substrate-recognition-landscapes-of-metalloproteases-using-comprehensive-mutagenesis
#4
Colin A Kretz
Protease specificity is controlled by exosites, which capture and orient the substrate, and the active site, which binds substrate residues near the P1-P1' scissile bond and catalyzes peptide hydrolysis. Techniques used to identify critical contact points between a protease and its substrate can be time consuming and labor-intensive. Screening tools such as phage display have been revitalized with the emergence of high-throughput sequencing technology, and can be used to interrogate protease substrate specificity...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28209710/a-model-for-the-conformational-activation-of-the-structurally-quiescent-metalloprotease-adamts13-by-von-willebrand-factor
#5
Kieron South, Marta O Freitas, David A Lane
Blood loss is prevented by the multidomain glycoprotein von Willebrand factor (VWF), which binds exposed collagen at damaged vessels and captures platelets. VWF is regulated by the metalloprotease ADAMTS13, which in turn is conformationally activated by VWF. To delineate the structural requirements for VWF-mediated conformational activation of ADAMTS13, we performed binding and functional studies with a panel of truncated ADAMTS13 variants. We demonstrate that both the isolated CUB1 and CUB2 domains in ADAMTS13 bind to the spacer domain exosite of a truncated ADAMTS13 variant, MDTCS (KD of 135 ± 1 0...
April 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28167788/crystal-structure-of-the-adenosine-a2a-receptor-bound-to-an-antagonist-reveals-a-potential-allosteric-pocket
#6
Bingfa Sun, Priti Bachhawat, Matthew Ling-Hon Chu, Martyn Wood, Tom Ceska, Zara A Sands, Joel Mercier, Florence Lebon, Tong Sun Kobilka, Brian K Kobilka
The adenosine A2A receptor (A2AR) has long been implicated in cardiovascular disorders. As more selective A2AR ligands are being identified, its roles in other disorders, such as Parkinson's disease, are starting to emerge, and A2AR antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A2A receptor bound to compound 1 (Cmpd-1), a novel A2AR/N-methyl d-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28060820/proteolytic-origin-of-the-soluble-human-il-6r-in-vivo-and-a-decisive-role-of-n-glycosylation
#7
Steffen Riethmueller, Prasath Somasundaram, Johanna C Ehlers, Chien-Wen Hung, Charlotte M Flynn, Juliane Lokau, Maria Agthe, Stefan Düsterhöft, Yijue Zhu, Joachim Grötzinger, Inken Lorenzen, Tomas Koudelka, Kosuke Yamamoto, Ute Pickhinke, Rielana Wichert, Christoph Becker-Pauly, Marisa Rädisch, Alexander Albrecht, Markus Hessefort, Dominik Stahnke, Carlo Unverzagt, Stefan Rose-John, Andreas Tholey, Christoph Garbers
Signaling of the cytokine interleukin-6 (IL-6) via its soluble IL-6 receptor (sIL-6R) is responsible for the proinflammatory properties of IL-6 and constitutes an attractive therapeutic target, but how the sIL-6R is generated in vivo remains largely unclear. Here, we use liquid chromatography-mass spectrometry to identify an sIL-6R form in human serum that originates from proteolytic cleavage, map its cleavage site between Pro-355 and Val-356, and determine the occupancy of all O- and N-glycosylation sites of the human sIL-6R...
January 2017: PLoS Biology
https://www.readbyqxmd.com/read/28059082/nmr-reveals-a-dynamic-allosteric-pathway-in-thrombin
#8
Lindsey D Handley, Brian Fuglestad, Kyle Stearns, Marco Tonelli, R Bryn Fenwick, Phineus R L Markwick, Elizabeth A Komives
Although serine proteases are found ubiquitously in both eukaryotes and prokaryotes, and they comprise the largest of all of the peptidase families, their dynamic motions remain obscure. The backbone dynamics of the coagulation serine protease, apo-thrombin (S195M-thrombin), were compared to the substrate-bound form (PPACK-thrombin). R1, R2, (15)N-{(1)H}NOEs, and relaxation dispersion NMR experiments were measured to capture motions across the ps to ms timescale. The ps-ns motions were not significantly altered upon substrate binding...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28007598/identification-of-acap5-as-a-novel-factor-xa-inhibitor-with-both-direct-and-allosteric-inhibition
#9
Yuanjun Zhu, Yuan Lin, Xiaoyan Liu, Wenhui Hu, Yinye Wang
Ancylostoma caninum anticoagulant peptide 5 (AcAP5) is a potent inhibitor for coagulation factor Xa (FXa). Previous studies show that AcAP5 binds to FXa at the active site, and/or the exosite. The active site-binding contributes to direct blocking of FXa catalytic activity, but the effect of exosite-binding and the underlying mechanism remain unknown. To investigate whether and how the exosite-binding affects FXa function, we prepared several AcAP5 mutants with modifications to the active site-binding or exosite-binding region...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27975099/paradoxical-bleeding-and-thrombotic-episodes-of-dysprothrombinaemia-due-to-a-homozygous-arg382his-mutation
#10
Qiulan Ding, Likui Yang, Xiaoqing Zhao, Wenman Wu, Xuefeng Wang, Alireza R Rezaie
We have characterised the pathogenic basis of dysprothrombinaemia in a patient exhibiting paradoxical bleeding and thrombotic defects during pregnancy and postpartum. Genetic analysis revealed that the proband is homozygous for the prothrombin Arg382His mutation, possessing only ~1 % clotting activity. The proband experienced severe bleeding episodes during her pregnancy, which required treatment with prothrombin complex concentrates, and then pulmonary embolism and deep-vein thrombosis at 28 days postpartum, which required treatment with LMWH and fresh frozen plasma...
February 28, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/27920432/discovery-of-an-enzyme-and-substrate-selective-inhibitor-of-adam10-using-an-exosite-binding-glycosylated-substrate
#11
Franck Madoux, Daniela Dreymuller, Jean-Phillipe Pettiloud, Radleigh Santos, Christoph Becker-Pauly, Andreas Ludwig, Gregg B Fields, Thomas Bannister, Timothy P Spicer, Mare Cudic, Louis D Scampavia, Dmitriy Minond
ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recent years, there has been a shift from active site to secondary substrate binding site (exosite) inhibitor discovery in order to identify non-zinc-binding molecules. In the present work a glycosylated, exosite-binding substrate of ADAM10 and ADAM17 was utilized to screen 370,276 compounds from the MLPCN collection...
December 2016: Scientific Reports
https://www.readbyqxmd.com/read/27909054/identification-of-a-substrate-selective-exosite-within-the-metalloproteinase-anthrax-lethal-factor
#12
Allison B Goldberg, Eunice Cho, Chad J Miller, Hua Jane Lou, Benjamin E Turk
The metalloproteinase anthrax lethal factor (LF) is secreted by Bacillus anthracis to promote disease virulence through disruption of host signaling pathways. LF is a highly specific protease, exclusively cleaving mitogen-activated protein kinase kinases (MKKs) and rodent NLRP1B (NACHT leucine-rich repeat and pyrin domain-containing protein 1B). How LF achieves such restricted substrate specificity is not understood. Previous studies have suggested the existence of an exosite interaction between LF and MKKs that promotes cleavage efficiency and specificity...
January 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27904902/a-novel-hirudin-derivative-inhibiting-thrombin-without-bleeding-for-subcutaneous-injection
#13
Bing Zhao, Yanling Zhang, Yinong Huang, Jinchao Yu, Yaran Li, Qi Wang, Yixin Ma, Hou-Yan Song, Min Yu, Wei Mo
Currently, anticoagulants would be used to prevent thrombosis. Thrombin is an effector enzyme for haemostasis and thrombosis. We designed a direct thrombin inhibitor peptide (DTIP) using molecular simulation and homology modelling and demonstrated that the C-terminus of DTIP interacts with exosite I, and N-terminus with the activity site of thrombin, respectively. DTIP interfered with thrombin-mediated coagulation in human, rat and mouse plasma (n=10 per group) and blocked clotting in human whole blood in vitro...
December 1, 2016: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/27899589/through-bond-effects-in-the-ternary-complexes-of-thrombin-sandwiched-by-two-dna-aptamers
#14
Andrea Pica, Irene Russo Krauss, Valeria Parente, Hisae Tateishi-Karimata, Satoru Nagatoishi, Kouhei Tsumoto, Naoki Sugimoto, Filomena Sica
Aptamers directed against human thrombin can selectively bind to two different exosites on the protein surface. The simultaneous use of two DNA aptamers, HD1 and HD22, directed to exosite I and exosite II respectively, is a very powerful approach to exploit their combined affinity. Indeed, strategies to link HD1 and HD22 together have been proposed in order to create a single bivalent molecule with an enhanced ability to control thrombin activity. In this work, the crystal structures of two ternary complexes, in which thrombin is sandwiched between two DNA aptamers, are presented and discussed...
January 9, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27794633/molecular-dynamics-simulations-of-aptamer-binding-reveal-generalized-allostery-in-thrombin
#15
Jiajie Xiao, Freddie R Salsbury
Thrombin is an attractive target for antithrombotic therapy due to its central role in thrombosis and hemostasis as well as its role in inducing tumor growth, metastasis, and tumor invasion. The thrombin-binding DNA aptamer (TBA), is under investigation for anticoagulant drugs. Although aptamer binding experiments have been revealed various effects on thrombin's enzymatic activities, the detailed picture of the thrombin's allostery from TBA binding is still unclear. To investigate thrombin's response to the aptamer-binding at the molecular level, we compare the mechanical properties and free energy landscapes of the free and aptamer-bound thrombin using microsecond-scale all-atom GPU-based molecular dynamics simulations...
November 29, 2016: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/27767076/direct-and-indirect-mechanisms-of-klk4-inhibition-revealed-by-structure-and-dynamics
#16
Blake T Riley, Olga Ilyichova, Mauricio G S Costa, Benjamin T Porebski, Simon J de Veer, Joakim E Swedberg, Itamar Kass, Jonathan M Harris, David E Hoke, Ashley M Buckle
The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 Å) resolution, as well as with bound nickel...
October 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27760842/molecular-mapping-of-%C3%AE-thrombin-%C3%AE-t-%C3%AE-2-glycoprotein-i-%C3%AE-2gpi-interaction-reveals-how-%C3%AE-2gpi-affects-%C3%AE-t-functions
#17
Laura Acquasaliente, Daniele Peterle, Simone Tescari, Nicola Pozzi, Vittorio Pengo, Vincenzo De Filippis
β2-Glycoprotein I (β2GpI) is the major autoantigen in the antiphospholipid syndrome, a thrombotic autoimmune disease. Nonetheless, the physiological role of β2GpI is still unclear. In a recent work, we have shown that β2GpI selectively inhibits the procoagulant functions of human α-thrombin (αT; i.e. prolongs fibrin clotting time, tc, and inhibits αT-induced platelet aggregation) without affecting the unique anticoagulant activity of the protease, i.e. the proteolytic generation of the anticoagulant protein C (PC) from the PC zymogen, which interacts with αT exclusively at the protease catalytic site...
December 15, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27722252/picolinic-acids-as-%C3%AE-exosite-inhibitors-of-botulinum-neurotoxin-a-light-chain
#18
Paul T Bremer, Song Xue, Kim D Janda
In developing small-molecule inhibitors of botulinum neurotoxin serotype A light chain (BoNT/A LC), substituted picolinic acids were identified. Extensive investigation into the SAR of the picolinic acid scaffold revealed 5-(1-butyl-4-chloro-1H-indol-2-yl)picolinic acid (CBIP), which possessed low micromolar activity against BoNT/A. Kinetic and docking studies demonstrated binding of CBIP to the β-exosite: a largely unexplored site on the LC that holds therapeutic relevance for botulism treatment.
October 13, 2016: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/27678152/in-silico-prediction-of-the-molecular-basis-of-cltx-and-aactx-interaction-with-matrix-metalloproteinase-2-mmp-2-to-inhibit-glioma-cell-invasion
#19
Houcemeddine Othman, Silke Andrea Wieninger, Mohamed ElAyeb, Michael Nilges, Najet Srairi-Abid
Glioblastoma is the deadliest type of brain cancer. Treatment could target the Matrix metalloproteinase-2 (MMP-2), which is known to be involved in the invasion process of glioblastoma cells. But current available inhibitors are not selective to MMP-2 due to their interaction with the catalytic binding site, which is highly conserved in all MMPs structures. Interestingly, members of the chloride channel blocker scorpion toxins, such as chlorotoxin (ClTx) and AaCTx, inhibit glioblastoma cell invasion and show a promising therapeutic potential...
September 28, 2016: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/27624125/thrombin-cleavage-of-plasmodium-falciparum-erythrocyte-membrane-protein-1-inhibits-cytoadherence
#20
Mark R Gillrie, Bernard Renaux, Eleanor Russell-Goldman, Marion Avril, Andrew J Brazier, Koichiro Mihara, Enrico Di Cera, Danny A Milner, Morley D Hollenberg, Joseph D Smith, May Ho
UNLABELLED: Plasmodium falciparum malaria remains one of the most deadly infections worldwide. The pathogenesis of the infection results from the sequestration of infected erythrocytes (IRBC) in vital organs, including the brain, with resulting impairment of blood flow, hypoxia, and lactic acidosis. Sequestration occurs through the adhesion of IRBC to host receptors on microvascular endothelium by Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a large family of variant surface antigens, each with up to seven extracellular domains that can bind to multiple host receptors...
September 13, 2016: MBio
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