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https://www.readbyqxmd.com/read/29688327/structural-and-biochemical-characterization-of-the-protease-domain-of-the-mosaic-botulinum-neurotoxin-type-ha
#1
Kwok-Ho Lam, Stefan Sikorra, Jasmin Weisemann, Hannah Maatsch, Kay Perry, Andreas Rummel, Thomas Binz, Rongsheng Jin
The extreme toxicity of botulinum neurotoxins (BoNTs) relies on their specific cleavage of SNARE proteins, which eventually leads to muscle paralysis. One newly identified mosaic toxin, BoNT/HA (aka H or FA), cleaves VAMP-2 at a unique position between residues L54 and E55, but the molecular basis underlying VAMP-2-recognition of BoNT/HA remains poorly characterized. Here, we report a ∼2.09 Å resolution crystal structure of the light chain protease domain of BoNT/HA (LC/HA). Structural comparison between LC/HA and LC of BoNT/F1 (LC/F1) reveals distinctive hydrophobic and electrostatic features near the active sites, which may explain their different VAMP-2 cleavage sites...
April 23, 2018: Pathogens and Disease
https://www.readbyqxmd.com/read/29676173/biomolecular-basis-of-matrix-metallo-proteinase-9-activity
#2
Rayala Swetha, Chandrim Gayen, Devendra Kumar, Tryambak Deo Singh, Gyan Modi, Sushil Kumar Singh
Matrix metalloproteinases (MMPs) are structurally related endopeptidases. They are also known as metzincins due to their interaction with zinc ion of the conserved methionine (Met) at the active site. MMPs play an important role in physiological and signaling processes of wound healing, bone resorption and angiogenesis. The structure of MMPs consists of signal peptide, propeptide, catalytic domain, hinge region and hemopexin-like domain. MMP-9 shares high structural and functional similarities with MMP-2, therefore designing selective MMP-9 inhibitors (MMPIs) is challenging...
April 20, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29666272/human-n-acetylglucosaminyltransferase-ii-substrate-recognition-uses-a-modular-architecture-that-includes-a-convergent-exosite
#3
Renuka Kadirvelraj, Jeong-Yeh Yang, Justin H Sanders, Lin Liu, Annapoorani Ramiah, Pradeep Kumar Prabhakar, Geert-Jan Boons, Zachary A Wood, Kelley W Moremen
Asn-linked oligosaccharides are extensively modified during transit through the secretory pathway, first by trimming of the nascent glycan chains and subsequently by initiating and extending multiple oligosaccharide branches from the trimannosyl glycan core. Trimming and branching pathway steps are highly ordered and hierarchal based on the precise substrate specificities of the individual biosynthetic enzymes. A key committed step in the synthesis of complex-type glycans is catalyzed by N -acetylglucosaminyltransferase II (MGAT2), an enzyme that generates the second GlcNAcβ1,2- branch from the trimannosyl glycan core using UDP-GlcNAc as the sugar donor...
April 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29649434/evaluation-of-an-allosteric-bace-inhibitor-peptide-to-identify-mimetics-that-can-interact-with-the-loop-f-region-of-the-enzyme-and-prevent-app-cleavage
#4
Jesus Campagna, Kanagasabai Vadivel, Barbara Jagodzinska, Michael Jun, Tina Bilousova, Patricia Spilman, Varghese John
The aspartyl protease BACE1 (BACE) has emerged as an appealing target for reduction of amyloid-β (Aβ) in Alzheimer's disease (AD). The clinical fate of active-site BACE inhibitors may depend on potential side effects related to enzyme- and substrate-selectivity. One strategy to reduce this risk is through development of allosteric inhibitors that interact with and modulate the Loop F region unique to BACE1. Previously, a BACE-inhibiting antibody (Ab) was shown by co-crystallization to bind and induce conformational changes of Loop F, resulting in backbone perturbations at the distal S6 and S7 subsites, preventing proper binding of a long APP-like substrate to BACE and inhibiting its cleavage...
April 9, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29594414/aptamer-functionalized-magnetic-and-fluorescent-nanospheres-for-one-step-sensitive-detection-of-thrombin
#5
Cong-Ying Wen, Jia-Hui Bi, Ling-Ling Wu, Jing-Bin Zeng
A one-step sandwich method is described for detecting proteins with magnetic nanospheres (MNs) and fluorescent nanospheres (FNs). Thrombin is selected as a model analyte to validate the method. Two DNA aptamers (Apt 29 and Apt 15 targeting two different exosites of thrombin) are chosen as recognition elements to modify MNs and FNs. The superparamagnetic MN-Apt 29 conjugate is used to separate and concentrate thrombin. The FN-Apt 15 conjugate encapsulates hundreds of fluorescent quantum dots and is used as reporter to provide a stable signal...
December 22, 2017: Mikrochimica Acta
https://www.readbyqxmd.com/read/29573721/novel-heparin-mimetics-reveal-cooperativity-between-exosite-2-and-sodium-binding-site-of-thrombin
#6
May H Abdel Aziz, Umesh R Desai
INTRODUCTION: Thrombin is a primary target of most anticoagulants. Yet, thrombin's dual and opposing role in pro- as well as anti- coagulant processes imposes considerable challenges in discovering finely tuned regulators that maintain homeostasis, rather than disproportionately changing the equilibrium to one side. In this connection, we have been studying exosite 2-mediated allosteric modulation of thrombin activity using synthetic agents called low molecular weight lignins (LMWLs)...
March 17, 2018: Thrombosis Research
https://www.readbyqxmd.com/read/29532595/factor-xa-and-viia-inhibition-by-tissue-factor-pathway-inhibitor-is-prevented-by-a-monoclonal-antibody-to-its-kunitz-1-domain
#7
C Augustsson, A Svensson, B Kjaer, T-Y Chao, X Wenjuan, B O Krogh, J Breinholt, J T Clausen, I Hilden, H H Petersen, L C Petersen
Essentials Activated FVII (FVIIa) and FX (FXa) are inhibited by tissue factor pathway inhibitor (TFPI). A monoclonal antibody, mAb2F22, was raised against the N-terminal fragment of TFPI (1-79). mAb2F22 bound exclusively to the K1 domain of TFPI (KD ∼1 nm) and not to the K2 domain. mAb2F22 interfered with inhibition of both FVIIa and FXa activities and restored clot formation. SUMMARY: Background Initiation of coagulation is induced by binding of activated factor VII (FVIIa) to tissue factor (TF) and activation of factor X (FX) in a process regulated by tissue factor pathway inhibitor (TFPI)...
May 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29499943/thermodynamic-anticoagulant-and-antiproliferative-properties-of-thrombin-binding-aptamer-containing-novel-una-derivative
#8
Weronika Kotkowiak, Jolanta Lisowiec-Wachnicka, Jakub Grynda, Ryszard Kierzek, Jesper Wengel, Anna Pasternak
Thrombin is a serine protease that plays a crucial role in hemostasis, fibrinolysis, cell proliferation, and migration. Thrombin binding aptamer (TBA) is able to inhibit the activity of thrombin molecule via binding to its exosite I. This 15-nt DNA oligonucleotide forms an intramolecular, antiparallel G-quadruplex structure with a chair-like conformation. In this paper, we report on our investigations on the influence of certain modified nucleotide residues on thermodynamic stability, folding topology, and biological properties of TBA variants...
March 2, 2018: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29494334/kallikrein-related-peptidase-14-is-the-second-klk-protease-targeted-by-the-serpin-vaspin
#9
David Ulbricht, Catherine A Tindall, Kathrin Oertwig, Stefanie Hanke, Norbert Sträter, John T Heiker
Kallikrein-related peptidases KLK5, KLK7 and KLK14 are important proteases in skin desquamation and aberrant KLK activity is associated with inflammatory skin diseases such as Netherton syndrome but also with various serious forms of cancer. Previously, we have identified KLK7 as the first protease target of vaspin (Serpin A12). Here, we report KLK14 as a second KLK protease to be inhibited by vaspin. In conclusion, vaspin represents a multi-specific serpin targeting the kallikrein proteases KLK7 and KLK14, with distinct exosites regulating recognition of these target proteases and opposing effects of heparin binding on the inhibition reaction...
March 23, 2018: Biological Chemistry
https://www.readbyqxmd.com/read/29488211/monoclonal-antibodies-against-metzincin-targets
#10
REVIEW
Salvatore Santamaria, Rens de Groot
The metzincin clan of metalloproteinases includes the MMP, disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs families, which cleave extracellular targets in a wide range of (patho)physiological processes. Antibodies constitute a powerful tool to modulate the activity of these enzymes for both therapeutic and research purposes. In this review, we give an overview of monoclonal antibodies (mAbs) that have been tested in preclinical disease models, human trials and important studies of metzincin structure and function...
February 27, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29459207/a-small-group-of-sulfated-benzofurans-induces-steady-state-submaximal-inhibition-of-thrombin
#11
Daniel K Afosah, Stephen Verespy, Rami A Al-Horani, Rio S Boothello, Rajesh Karuturi, Umesh R Desai
Despite the development of promising direct oral anticoagulants, which are all orthosteric inhibitors, a sizable number of patients suffer from bleeding complications. We have hypothesized that allosterism based on the heparin-binding exosites presents a major opportunity to induce sub-maximal inhibition of coagulation proteases, thereby avoiding/reducing bleeding risk. We present the design of a group of sulfated benzofuran dimers that display heparin-binding site-dependent partial allosteric inhibition of thrombin against fibrinogen (ΔY = 55-75%), the first time that a small molecule (MW  < 800) has been found to thwart macromolecular cleavage by a monomeric protease in a controlled manner...
April 1, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29434246/high-throughput-protease-profiling-comprehensively-defines-active-site-specificity-for-thrombin-and-adamts13
#12
Colin A Kretz, Kärt Tomberg, Alexander Van Esbroeck, Andrew Yee, David Ginsburg
We have combined random 6 amino acid substrate phage display with high throughput sequencing to comprehensively define the active site specificity of the serine protease thrombin and the metalloprotease ADAMTS13. The substrate motif for thrombin was determined by >6,700 cleaved peptides, and was highly concordant with previous studies. In contrast, ADAMTS13 cleaved only 96 peptides (out of >107 sequences), with no apparent consensus motif. However, when the hexapeptide library was substituted into the P3-P3' interval of VWF73, an exosite-engaging substrate of ADAMTS13, 1670 unique peptides were cleaved...
February 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29420634/ligand-binding-modulates-the-structural-dynamics-and-activity-of-urokinase-type-plasminogen-activator-a-possible-mechanism-of-plasminogen-activation
#13
Tobias Kromann-Hansen, Eva Louise Lange, Ida K Lund, Gunilla Høyer-Hansen, Peter A Andreasen, Elizabeth A Komives
The catalytic activity of trypsin-like serine proteases is in many cases regulated by conformational changes initiated by binding of physiological modulators to exosites located distantly from the active site. A trypsin-like serine protease of particular interest is urokinase-type plasminogen activator (uPA), which is involved in extracellular tissue remodeling processes. Herein, we used hydrogen/deuterium exchange mass spectrometry (HDXMS) to study regulation of activity in the catalytic domain of the murine version of uPA (muPA) by two muPA specific monoclonal antibodies...
2018: PloS One
https://www.readbyqxmd.com/read/29419409/anticoagulant-protein-s-targets-the-factor-ixa-heparin-binding-exosite-to-prevent-thrombosis
#14
William E Plautz, Vijaya Satish Sekhar Pilli, Brian C Cooley, Rima Chattopadhyay, Pamela R Westmark, Todd Getz, David Paul, Wolfgang Bergmeier, John P Sheehan, Rinku Majumder
OBJECTIVE: PS (protein S) is a plasma protein that directly inhibits the coagulation FIXa (factor IXa) in vitro. Because elevated FIXa is associated with increased risk of venous thromboembolism, it is important to establish how PS inhibits FIXa function in vivo. The goal of this study is to confirm direct binding of PS with FIXa in vivo, identify FIXa amino acid residues required for binding PS in vivo, and use an enzymatically active FIXa mutant that is unable to bind PS to measure the significance of PS-FIXa interaction in hemostasis...
April 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29414788/extensive-peptide-and-natural-protein-substrate-screens-reveal-that-mouse-caspase-11-has-much-narrower-substrate-specificity-than-caspase-1
#15
Monica L Gonzalez Ramirez, Marcin Poreba, Scott J Snipas, Katarzyna Groborz, Marcin Drag, Guy S Salvesen
Inflammatory cell death, or pyroptosis, is triggered by pathogenic infections or events. It is executed by caspase-1 (in the canonical pyroptosis pathway) or caspase-11 (noncanonical pathway), each via production of a cell-lytic domain from the pyroptosis effector protein gasdermin D through specific and limited proteolysis. Pyroptosis is accompanied by the release of inflammatory mediators, including the proteolytically processed forms of interleukin-1β (IL-1β) and IL-18. Given the similar inflammatory outcomes of the canonical and noncanonical pyroptosis pathways, we hypothesized that caspase-1 and -11 should have very similar activities and substrate specificities...
February 6, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29396291/novel-structural-mechanism-of-allosteric-regulation-of-aspartic-peptidases-via-an-evolutionarily-conserved-exosite
#16
Iva Hánová, Jiří Brynda, Radka Houštecká, Nawsad Alam, Daniel Sojka, Petr Kopáček, Lucie Marešová, Jiří Vondrášek, Martin Horn, Ora Schueler-Furman, Michael Mareš
Pepsin-family aspartic peptidases are biosynthesized as inactive zymogens in which the propeptide blocks the active site until its proteolytic removal upon enzyme activation. Here, we describe a novel dual regulatory function for the propeptide using a set of crystal structures of the parasite cathepsin D IrCD1. In the IrCD1 zymogen, intramolecular autoinhibition by the intact propeptide is mediated by an evolutionarily conserved exosite on the enzyme core. After activation, the mature enzyme employs the same exosite to rebind a small fragment derived from the cleaved propeptide...
March 15, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29378358/chemical-footprinting-reveals-conformational-changes-following-activation-of-factor-xi
#17
Ingrid Stroo, J Arnoud Marquart, Kamran Bakhtiari, Tom Plug, Alexander B Meijer, Joost C M Meijers
Coagulation factor XI is activated by thrombin or factor XIIa resulting in a conformational change that converts the catalytic domain into its active form and exposing exosites for factor IX on the apple domains. Although crystal structures of the zymogen factor XI and the catalytic domain of the protease are available, the structure of the apple domains and hence the interactions with the catalytic domain in factor XIa are unknown. We now used chemical footprinting to identify lysine residue containing regions that undergo a conformational change following activation of factor XI...
February 2018: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/29355554/dual-inhibition-of-hy023016-based-on-binding-properties-of-platelet-membrane-receptor-subunit-glycoprotein-ib%C3%AE-and-thrombin-exosites
#18
Qiu-Fang Chen, Shuang Cui, Hui-Liang Shen, Xiang Chen, Yun-Zhan Li, Qian Wu, Yun-Gen Xu, Guo-Qing Gong
Thrombin has long been suggested as a desirable antithrombotic target, but anti-thrombin therapy without anti-platelet thereby has never achieved the ideal effect. HY023016 is a novel compound, in our previous study, it exerted better anti-thrombotic than dabigatran etexilate. The present study aims to illustrate the excess anti-thrombotic molecular mechanisms of HY023016 through thrombin anion exosites and the platelet membrane receptor subunit glycoprotein Ibα (GPIbα). HY023016 strongly inhibited the conversion of fibrinogen to fibrous may via blocking thrombin exosite I...
March 5, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29301478/new-substituted-aminopyrimidine-derivatives-as-bace1-inhibitors-in-silico-design-synthesis-and-biological-assays
#19
Lucas J Gutiérrez, Oscar Parravicini, Emilse Sánchez, Ricaurte Rodríguez, Justo Cobo, Ricardo D Enriz
We report in this work new substituted aminopyrimidine derivatives acting as inhibitors of the catalytic site of BACE1. These compounds were obtained from a molecular modeling study. The theoretical and experimental study reported here was carried out in several steps: docking analysis, Molecular Dynamics (MD) simulations, Quantum Theory Atom in Molecules (QTAIM) calculations, synthesis and bioassays and has allowed us to propose some compounds of this series as new inhibitors of the catalytic site of BACE1...
February 1, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29184120/halistanol-sulfates-i-and-j-new-sirt1-3-inhibitory-steroid-sulfates-from-a-marine-sponge-of-the-genus-halichondria
#20
Fumiaki Nakamura, Norio Kudo, Yuki Tomachi, Akiko Nakata, Misao Takemoto, Akihiro Ito, Hodaka Tabei, Daisuke Arai, Nicole de Voogd, Minoru Yoshida, Yoichi Nakao, Nobuhiro Fusetani
Two new analogs of halistanol sulfate (1) were isolated from a marine sponge Halichondria sp. collected at Hachijo-jima Island. Structures of these new halistanol sulfates I (2) and J (3) were elucidated by spectral analyses. Compounds 1-3 showed inhibitory activity against SIRT 1-3 with IC50 ranges of 45.9-67.9, 18.9-21.1 and 21.8-37.5 μM, respectively. X-ray crystallography of the halistanol sulfate (1) and SIRT3 complex clearly indicates that 1 binds to the exosite of SIRT3 that we have discovered in this study...
February 2018: Journal of Antibiotics
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