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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 modelling 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...
January 4, 2018: Journal of Biomolecular Structure & Dynamics
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...
November 29, 2017: Journal of Antibiotics
Raheel Ahmad, Ghulam Destgeer, Muhammad Afzal, Jinsoo Park, Husnain Ahmed, Jin Ho Jung, Kwangseok Park, Tae-Sung Yoon, Hyung Jin Sung
We developed a hybrid microfluidic device that utilized acoustic waves to drive functionalized microparticles inside a continuous flow microchannel and to separate particle-conjugated target proteins from a complex fluid. The acoustofluidic device comprised of an interdigitated transducer (IDT) that produced high-frequency surface acoustic waves (SAW) in a polydimethylsiloxane (PDMS) microfluidic channel. The SAW interacted with the sample fluid flow inside the microchannel and deflected particles from their original streamlines to achieve separation...
November 17, 2017: Analytical Chemistry
Ramya Billur, David Ban, T Michael Sabo, Muriel Christine Maurer
Thrombin participates in procoagulation, anticoagulation, and platelet activation. This enzyme contains anion binding exosites, ABE I and ABE II, which attract regulatory biomolecules. As prothrombin is activated to thrombin, pro-ABE I is converted into mature ABE I. Unexpectedly, certain ligands can bind to pro-ABE I specifically. Moreover, knowledge is lacking on changes in conformation and affinity that occur at the individual residue level as pro-ABE I is converted to ABE I. Such changes are transient and failed to be captured by crystallography...
November 7, 2017: Biochemistry
Enrico Guarnera, Zhen Wah Tan, Zejun Zheng, Igor N Berezovsky
Motivation: Allostery is an omnipresent mechanism of the function modulation in proteins via either effector binding or mutations in the exosites. Despite the growing number of online servers and databases devoted to prediction/classification of allosteric sites and their characteristics, there is a lack of resources for an efficient and quick estimation of the causality and energetics of allosteric communication. Results: The AlloSigMA server implements a unique approach on the basis of the recently introduced structure-based statistical mechanical models of allosteric signaling...
July 6, 2017: Bioinformatics
F Xavier Gomis-Rüth
Drug candidates against matrix metalloproteinases (MMPs) failed in the clinic in the past because their strong zinc-targeting warheads led to a lack of specificity. More recently, significant selectivity among MMPs was achieved by blocking the enzymes' specificity pockets, nearby exosites, and downstream domains. Scannevin and colleagues now elegantly twist the plot and achieve ultimate selectivity: They target MMP-9 by allosterically preventing activation of its zymogen.
October 27, 2017: Journal of Biological Chemistry
Siew Siew Pang, Lakshmi C Wijeyewickrema, Lilian Hor, Sheareen Tan, Emilie Lameignere, Edward M Conway, Anna M Blom, Frida C Mohlin, Xuyu Liu, Richard J Payne, James C Whisstock, Robert N Pike
Complement is crucial to the immune response, but dysregulation of the system causes inflammatory disease. Complement is activated by three pathways: classical, lectin, and alternative. The classical and lectin pathways are initiated by the C1r/C1s (classical) and MASP-1/MASP-2 (lectin) proteases. Given the role of complement in disease, there is a requirement for inhibitors to control the initiating proteases. In this article, we show that a novel inhibitor, gigastasin, from the giant Amazon leech, potently inhibits C1s and MASP-2, whereas it is also a good inhibitor of MASP-1...
October 23, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Song Xue, Hajime Seki, Marek Remes, Peter Šilhár, Kim Janda
Botulinum neurotoxins (BoNT) are among the most toxic known substances and currently there are no effective treatments for intraneuronal BoNT intoxication. Chicoric acid (ChA) was previously reported as a BoNT/A inhibitor that binds to the enzyme's α-exosite. Herein, we report the synthesis and structure-activity relationships (SARs) of a series of ChA derivatives, which revealed essential binding interactions between ChA and BoNT/A. Moreover, several ChA-based inhibitors with improved potency against the BoNT/A were discovered...
November 15, 2017: Bioorganic & Medicinal Chemistry Letters
Quintin W Hughes, Bao T Le, Grace Gilmore, Ross I Baker, Rakesh N Veedu
Aptamers are short synthetic DNA or RNA oligonucleotides that adopt secondary and tertiary conformations based on Watson-Crick base-pairing interactions and can be used to target a range of different molecules. Two aptamers, HD1 and HD22, that bind to exosites I and II of the human thrombin molecule, respectively, have been extensively studied due to their anticoagulant potentials. However, a fundamental issue preventing the clinical translation of many aptamers is degradation by nucleases and reduced pharmacokinetic properties requiring higher dosing regimens more often...
October 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Vincent Frappier, Madeleine Duran, Amy E Keating
PixelDB, the Peptide Exosite Location Database, compiles 1966 non-redundant, high-resolution structures of protein-peptide complexes filtered to minimize the impact of crystal packing on peptide conformation. The database is organized to facilitate study of structurally conserved vs. non-conserved elements of protein-peptide engagement. PixelDB clusters complexes based on the structural similarity of the peptide-binding protein, and by comparing complexes within a cluster highlights examples of domains that engage peptides using more than one binding mode...
October 12, 2017: Protein Science: a Publication of the Protein Society
Nadine Ruderisch, Daniel Schlatter, Andreas Kuglstatter, Wolfgang Guba, Sylwia Huber, Carlo Cusulin, Jörg Benz, Arne Christian Rufer, Joerg Hoernschemeyer, Christophe Schweitzer, Tina Bülau, Achim Gärtner, Eike Hoffmann, Jens Niewoehner, Christoph Patsch, Karlheinz Baumann, Hansruedi Loetscher, Eric Kitas, Per-Ola Freskgård
Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties...
October 2017: EBioMedicine
Michael Shokhen, Amnon Albeck
Rhomboid proteases constitute a family of intramembrane serine proteases ubiquitous in all forms of life. They differ in many aspects from their soluble counterparts. We applied molecular dynamics (MD) computational approach to address several challenging issues regarding their catalytic mechanism: How does the exosite of GlpG rhomboid protease control the kinetics efficiency of substrate hydrolysis? What is the mechanism of inhibition by the non-competitive peptidyl aldehyde inhibitors bound to the GlpG rhomboid active site (AS)? What is the underlying mechanism that explains the hypothesis that GlpG rhomboid protease is not adopted for the hydrolysis of short peptides that do not contain a transmembrane domain (TMD)? Two fundamental features of rhomboid catalysis, the enzyme recognition and discrimination of substrates by TMD interactions in the exosite, and the concerted mechanism of non-covalent pre-catalytic complex to covalent tetrahedral complex (TC) conversion, provide answers to these mechanistic questions...
September 8, 2017: Protein Science: a Publication of the Protein Society
Cyrielle Martini, Mikaël Bédard, Pierre Lavigne, Jean-Bernard Denault
Caspases are cysteinyl peptidases involved in inflammation and apoptosis during which hundreds of proteins are cleaved by executioner caspase-3 and -7. Despite the fact that caspase-3 has a higher catalytic activity, caspase-7 is more proficient at cleaving poly(ADP ribose) polymerase 1 (PARP1) because it uses an exosite within its N-terminal domain (NTD). Here, we demonstrate that molecular determinants also located in the NTD enhance the recognition and proteolysis of the Hsp90 co-chaperone p23. Structure-activity relationship analyses using mutagenesis of the caspase-7 NTD and kinetics show that residues 36-45 of caspase-7, which overlap with residues necessary for efficacious PARP1 cleavage, participate in p23 recognition...
September 26, 2017: Biochemistry
V S De Paula, F H S Silva, I M B Francischetti, R Q Monteiro, A P Valente
Ixolaris is a two-Kunitz tick salivary gland protein identified in Ixodes scapularis that presents sequence homology to TFPI (tissue factor pathway inhibitor). It binds to the coagulation enzyme factor Xa (FXa) or to its zymogen form, FX, and further inhibits tissue factor/FVIIa complex (extrinsic Xnase compex). Differently from TFPI, Ixolaris does not bind to the active site cleft of FXa. Instead, complex formation is mediated by the FXa heparin-binding exosite, which may also results in decreased FXa activity into the prothrombinase complex...
October 2017: Biomolecular NMR Assignments
Robert E Thompson, Xuyu Liu, Jorge Ripoll-Rozada, Noelia Alonso-García, Benjamin L Parker, Pedro José Barbosa Pereira, Richard J Payne
Madanin-1 and chimadanin are two small cysteine-free thrombin inhibitors that facilitate blood feeding in the tick Haemaphysalis longicornis. Here, we report a post-translational modification-tyrosine sulfation-of these two proteins that is critical for potent anti-thrombotic and anticoagulant activity. Inhibitors produced in baculovirus-infected insect cells displayed heterogeneous sulfation of two tyrosine residues within each of the proteins. One-pot ligation-desulfurization chemistry enabled access to homogeneous samples of all possible sulfated variants of the proteins...
September 2017: Nature Chemistry
Omid Zarei, Silvia Benvenuti, Fulya Ustun-Alkan, Maryam Hamzeh-Mivehroud, Siavoush Dastmalchi
RON (Recepteur d'Origine Nantais) tyrosine kinase receptor is a promising target for therapeutic intervention in cancer therapy. The aim of this work was identification of RON-binding peptides using phage display and computational modeling their mode of binding. A 12-mer peptide phage library was utilized to perform biopanning against RON. The RON-binding ability of the selected peptide-displaying phage and their possible binding sites were examined by ELISA. Binding modes and affinities were also predicted by docking and molecular dynamics (MD) simulation...
August 19, 2017: Journal of Molecular Modeling
Jiang Zhang, Rachel R Ogorzalek Loo, Joseph A Loo
Native mass spectrometry (MS) with electrospray ionization (ESI) has evolved as an invaluable tool for the characterization of intact native proteins and non-covalently bound protein complexes. Here we report the structural characterization by high resolution native top-down MS of human thrombin and its complex with the Bock thrombin binding aptamer (TBA), a 15-nucleotide DNA with high specificity and affinity for thrombin. Accurate mass measurements revealed that the predominant form of native human α-thrombin contains a glycosylation mass of 2205 Da, corresponding to a sialylated symmetric biantennary oligosaccharide structure without fucosylation...
July 28, 2017: Journal of the American Society for Mass Spectrometry
V S De Paula, F H S Silva, I M B Francischetti, R Q Monteiro, A P Valente
Ixolaris is an anticoagulant protein identified in the tick saliva of Ixodes scapularis. Ixolaris contains 2 Kunitz like domains and binds to Factor Xa or Factor X as a scaffold for inhibition of the Tissue Factor (TF)/Factor VIIa (FVIIa). In contrast to tissue factor pathway inhibitor (TFPI), however, Ixolaris does not bind to the active site cleft of FXa. Instead, complex formation is mediated by the FXa heparin-binding exosite. Due to its potent and long-lasting antithrombotic activity, Ixolaris is a promising agent for anticoagulant therapy...
November 2017: Protein Expression and Purification
Chengliang Wu, Alan R Stafford, James C Fredenburgh, Jeffrey I Weitz, Ann Gils, Paul J Declerck, Paul Y Kim
The thrombin-thrombomodulin (TM) complex activates thrombin-activable fibrinolysis inhibitor (TAFI) more efficiently than thrombin alone. The exosite on TAFI required for its TM-dependent activation by thrombin has not been identified. Based on previous work by us and others, we generated TAFI variants with one or more of residues Lys 42, Lys 43, Lys 44 and Arg 12 within the activation peptide mutated to alanine. Mutation of one, two, or three Lys residues or the Arg residue alone decreased the catalytic efficiency of TAFI activation by thrombin-TM by 2...
July 26, 2017: Thrombosis and Haemostasis
Sabrina Amar, Dmitriy Minond, Gregg B Fields
Remodeling of the extracellular matrix (ECM) is crucial in development and homeostasis, but also has a significant role in disease progression. Two metalloproteinase families, the matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs), participate in the remodeling of the ECM, either directly or through the liberation of growth factors and cell surface receptors. The correlation of MMP and ADAM activity to a variety of diseases has instigated numerous drug development programs. However, broad-based and Zn(2+) -chelating MMP and ADAM inhibitors have fared poorly in the clinic...
June 14, 2017: Proteomics
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