keyword
https://read.qxmd.com/read/37819980/phage-display-uncovers-a-sequence-motif-that-drives-polypeptide-binding-to-a-conserved-regulatory-exosite-of-o-glcnac-transferase
#21
JOURNAL ARTICLE
Matthew G Alteen, Richard W Meek, Subramania Kolappan, Jil A Busmann, Jessica Cao, Zoe O'Gara, Ying Chou, Ratmir Derda, Gideon J Davies, David J Vocadlo
The modification of nucleocytoplasmic proteins by O -linked N-acetylglucosamine ( O -GlcNAc) is an important regulator of cell physiology. O -GlcNAc is installed on over a thousand proteins by just one enzyme, O -GlcNAc transferase (OGT). How OGT is regulated is therefore a topic of interest. To gain insight into these questions, we used OGT to perform phage display selection from an unbiased library of ~109 peptides of 15 amino acids in length. Following rounds of selection and deep mutational panning, we identified a high-fidelity peptide consensus sequence, [Y/F]-x-P-x-Y-x-[I/M/F], that drives peptide binding to OGT...
October 17, 2023: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/37708351/exploiting-chemical-protein-synthesis-to-study-the-role-of-tyrosine-sulfation-on-anticoagulants-from-hematophagous-organisms
#22
JOURNAL ARTICLE
Joshua W C Maxwell, Paige M E Hawkins, Emma E Watson, Richard J Payne
ConspectusTyrosine sulfation is a post-translational modification (PTM) that modulates function by mediating key protein-protein interactions. One of the early proteins shown to possess this PTM was hirudin, produced in the salivary glands of the medicinal leech Hirudo medicinalis , whereby tyrosine sulfation led to a ∼10-fold improvement in α-thrombin inhibitory activity. Outside of this pioneering discovery, the involvement of tyrosine sulfation in modulating the activity of salivary proteins from other hematophagous organisms was unknown...
September 14, 2023: Accounts of Chemical Research
https://read.qxmd.com/read/37688791/phytocystatin-6-is-a-context-dependent-tight-binding-inhibitor-of-arabidopsis-thaliana-legumain-isoform-%C3%AE
#23
JOURNAL ARTICLE
Naiá P Santos, Wai Tuck Soh, Fatih Demir, Raimund Tenhaken, Peter Briza, Pitter F Huesgen, Hans Brandstetter, Elfriede Dall
Plant legumains are crucial for processing seed storage proteins and are critical regulators of plant programmed cell death. Although research on legumains boosted recently, little is known about their activity regulation. In our study, we used pull-down experiments to identify AtCYT6 as a natural inhibitor of legumain isoform β (AtLEGβ) in Arabidopsis thaliana. Biochemical analysis revealed that AtCYT6 inhibits both AtLEGβ and papain-like cysteine proteases through two separate cystatin domains...
September 9, 2023: Plant Journal
https://read.qxmd.com/read/37628902/crystal-structure-of-the-catalytic-domain-of-a-botulinum-neurotoxin-homologue-from-enterococcus-faecium-potential-insights-into-substrate-recognition
#24
JOURNAL ARTICLE
Kyle S Gregory, Peter-Rory Hall, Jude Prince Onuh, Otsile O Mojanaga, Sai Man Liu, K Ravi Acharya
Clostridium botulinum neurotoxins (BoNTs) are the most potent toxins known, causing the deadly disease botulism. They function through Zn2+ -dependent endopeptidase cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, preventing vesicular fusion and subsequent neurotransmitter release from motor neurons. Several serotypes of BoNTs produced by Clostridium botulinum (BoNT/A-/G and/X) have been well-characterised over the years. However, a BoNT-like gene (homologue of BoNT) was recently identified in the non-clostridial species, Enterococcus faecium, which is the leading cause of hospital-acquired multi-drug resistant infections...
August 12, 2023: International Journal of Molecular Sciences
https://read.qxmd.com/read/37562488/the-protease-associated-pa-domain-in-scpa-from-streptococcus-pyogenes-plays-a-role-in-substrate-recruitment
#25
JOURNAL ARTICLE
Sophie McKenna, Frances Aylward, Xeni Miliara, Rikin J Lau, Camilla Berg Huemer, Sean P Giblin, Kristin K Huse, Mingyang Liang, Lucy Reeves, Max Pearson, Yingqi Xu, Sarah L Rouse, James E Pease, Shiranee Sriskandan, Todd F Kagawa, Jakki Cooney, Stephen Matthews
Annually, over 18 million disease cases and half a million deaths worldwide are estimated to be caused by Group A Streptococcus. ScpA (or C5a peptidase) is a well characterised member of the cell enveleope protease family, which possess a S8 subtilisin-like catalytic domain and a shared multi-domain architecture. ScpA cleaves complement factors C5a and C3a, impairing the function of these critical anaphylatoxins and disrupts complement-mediated innate immunity. Although the of high resolution of structure ScpA is known, the details of how it recognises its substrate are only just emerging...
August 8, 2023: Biochimica et Biophysica Acta. Proteins and Proteomics
https://read.qxmd.com/read/37556858/robust-design-of-effective-allosteric-activators-for-rsp5-e3-ligase-using-the-machine-learning-tool-proteinmpnn
#26
JOURNAL ARTICLE
Hsi-Wen Kao, Wei-Lin Lu, Meng-Ru Ho, Yu-Fong Lin, Yun-Jung Hsieh, Tzu-Ping Ko, Shang-Te Danny Hsu, Kuen-Phon Wu
We used the deep learning tool ProteinMPNN to redesign ubiquitin (Ub) as a specific and functionally stimulating/enhancing binder of the Rsp5 E3 ligase. We generated 20 extensively mutated─up to 37 of 76 residues─recombinant Ub variants (UbVs), named R1 to R20, displaying well-folded structures and high thermal stabilities. These UbVs can also form stable complexes with Rsp5, as predicted using AlphaFold2. Three of the UbVs bound to Rsp5 with low micromolar affinity, with R4 and R12 effectively enhancing the Rsp5 activity six folds...
August 9, 2023: ACS Synthetic Biology
https://read.qxmd.com/read/37503836/steric-hindrance-and-structural-flexibility-shape-the-functional-properties-of-a-guanine-rich-oligonucleotide
#27
JOURNAL ARTICLE
Romualdo Troisi, Valeria Napolitano, Emanuele Rossitto, Waleed Osman, Masanobu Nagano, Koji Wakui, Grzegorz M Popowicz, Keitaro Yoshimoto, Filomena Sica
Ligand/protein molecular recognition involves a dynamic process, whereby both partners require a degree of structural plasticity to regulate the binding/unbinding event. Here, we present the characterization of the interaction between a highly dynamic G-rich oligonucleotide, M08s-1, and its target protein, human α-thrombin. M08s-1 is the most active anticoagulant aptamer selected thus far. Circular dichroism and gel electrophoresis analyses indicate that both intramolecular and intermolecular G-quadruplex structures are populated in solution...
July 28, 2023: Nucleic Acids Research
https://read.qxmd.com/read/37502151/mapping-the-binding-interactions-between-human-gasdermin-d-and-human-caspase-1-using-carbene-footprinting
#28
JOURNAL ARTICLE
James R Lloyd, Antonio Biasutto, Katharina L Dürr, Ali Jazayeri, Jonathan T S Hopper, Neil J Oldham
Carbene footprinting is a recently developed mass spectrometry-based chemical labeling technique that probes protein interactions and conformation. Here, we use the methodology to investigate binding interactions between the protease human Caspase-1 (C285A) and full-length human Gasdermin D (hGSDMD), which are important in inflammatory cell death. GSDMD is cleaved by Caspase-1, releasing its N-terminal domain which oligomerizes in the membrane to form large pores, resulting in lytic cell death. Regions of reduced carbene labeling (masking), caused by protein binding, were observed for each partner in the presence of the other and were consistent with hCaspase-1 exosite and active-site interactions...
July 24, 2023: JACS Au
https://read.qxmd.com/read/37457835/dynamic-allostery-in-thrombin-a-review
#29
REVIEW
Elizabeth A Komives
Thrombin is a serine protease that catalyzes a large number of different reactions including proteolytic cleave of fibrinogen to make the fibrin clot (procoagulant activity), of the protease activated receptors (for cell signaling) and of protein C generating activated protein C (anticoagulant activity). Thrombin has an effector binding site called the anion binding exosite 1 that is allosterically coupled to the active site. In this review, we survey results from thermodynamic characterization of the allosteric coupling as well as hydrogen-deuterium exchange mass spectrometry to reveal which parts of the thrombin structure are changed upon effector binding and/or mutagenesis, and finally NMR spectroscopy to characterize the different timescales of motions elicited by the effectors...
2023: Frontiers in Molecular Biosciences
https://read.qxmd.com/read/37238665/the-interaction-of-factor-xa-and-ixa-with-non-activated-antithrombin-in-michaelis-complex-insights-from-enhanced-sampling-molecular-dynamics-simulations
#30
JOURNAL ARTICLE
Gábor Balogh, Zsuzsanna Bereczky
The interaction between coagulation factors Xa and IXa and the activated state of their inhibitor, antithrombin (AT),have been investigated using X-ray diffraction studies. However, only mutagenesis data are available for non-activated AT. Our aim was to propose a model based on docking and advanced-sampling molecular dynamics simulations that can reveal the conformational behavior of the systems when AT is not binding a pentasaccharide. We built the initial structure for non-activated AT-FXa and AT-FIXa complexes using HADDOCK 2...
May 6, 2023: Biomolecules
https://read.qxmd.com/read/37081852/inactivation-of-the-lysine-binding-sites-of-human-plasminogen-hpg-reveals-novel-structural-requirements-for-the-tight-hpg-conformation-m-protein-binding-and-rapid-activation
#31
JOURNAL ARTICLE
Yetunde A Ayinuola, Francis J Castellino
Accelerated activation of the human plasminogen zymogen (hPg) to two-chain active plasmin (hPm) is achieved following conformational changes induced by ligand-binding at the lysine-binding sites (LBSs) in four of the five hPg kringle domains. In this manner, pattern D skin-trophic strains of Group A streptococci (GAS), through the expression of surface plasminogen-binding M-protein (PAM), immobilize surface hPg, thereby enabling rapid hPg activation by GAS-secreted streptokinase (SK). Consequently, GAS enhances virulence by digesting extracellular and tight cellular junctional barriers using hPm activity...
2023: Frontiers in Molecular Biosciences
https://read.qxmd.com/read/37068593/structures-of-factor-xi-and-prekallikrein-bound-to-domain-6-of-high-molecular-weight-kininogen-reveals-alternate-domain-6-conformations-and-exosites
#32
JOURNAL ARTICLE
Chan Li, Awital Bar Barroeta, Szu Shen Wong, Hyo Jung Kim, Monika Pathak, Ingrid Dreveny, Joost C M Meijers, Jonas Emsley
BACKGROUND: High molecular weight kininogen (HK) circulates in plasma as a complex with zymogen prekallikrein (PK). HK is both substrate and co-factor for activated plasma kallikrein (PKa) and the principal exosite interactions occur between PK N-terminal apple domains and the C-terminal D6 domain of HK. OBJECTIVE: To determine the structure of the complex formed between PK apple domains and a HKD6 fragment and compare this to the FXI-HK complex. METHODS: We produced recombinant FXI and PK heavy chains (HC) spanning all four apple domains...
April 15, 2023: Journal of Thrombosis and Haemostasis: JTH
https://read.qxmd.com/read/36813235/the-c-terminal-domains-of-adamts1-contain-exosites-involved-in-its-proteoglycanase-activity
#33
JOURNAL ARTICLE
AlexanderFrederick Minns, Yawei Qi, Kazuhiro Yamamoto, Karen Lee, Josefin Ahnström, Salvatore Santamaria
A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs (ADAMTS1) is a protease involved in fertilization, cancer, cardiovascular development, and thoracic aneurysms. Proteoglycans such as versican and aggrecan have been identified as ADAMTS1 substrates and Adamts1 ablation in mice typically results in versican accumulation; however, previous qualitative studies have suggested that ADAMTS1 proteoglycanase activity is weaker than that of other family members such as ADAMTS4 and ADAMTS5. Here, we investigated the functional determinants of ADAMTS1 proteoglycanase activity...
February 20, 2023: Journal of Biological Chemistry
https://read.qxmd.com/read/36763907/structure-based-optimization-of-protease-inhibitor-interactions-to-enhance-specificity-of-human-stefin-a-against-falcipain-2-from-the-plasmodium-falciparum-3d7-strain
#34
JOURNAL ARTICLE
Subhoja Chakraborty, Sampa Biswas
The emergence of resistance in Plasmodium falciparum to frontline artemisinin-based combination therapies has raised global concerns and emphasized the identification of new drug targets for malaria. Cysteine protease falcipain-2 (FP2), involved in host hemoglobin degradation and instrumental in parasite survival, has long been proposed as a promising malarial drug target. However, designing active-site-targeted small-molecule inhibitors of FP2 becomes challenging due to their off-target specificity toward highly homologous human cysteine cathepsins...
February 10, 2023: Biochemistry
https://read.qxmd.com/read/36760748/identification-of-specific-carbonic-anhydrase-inhibitors-via-in-situ-click-chemistry-phage-display-and-synthetic-peptide-libraries-comparison-of-the-methods-and-structural-study
#35
JOURNAL ARTICLE
Michael Kugler, Martin Hadzima, Rastislav Dzijak, Robert Rampmaier, Pavel Srb, Lukáš Vrzal, Zdeněk Voburka, Pavel Majer, Pavlína Řezáčová, Milan Vrabel
The development of highly active and selective enzyme inhibitors is one of the priorities of medicinal chemistry. Typically, various high-throughput screening methods are used to find lead compounds from a large pool of synthetic compounds, and these are further elaborated and structurally refined to achieve the desired properties. In an effort to streamline this complex and laborious process, new selection strategies based on different principles have recently emerged as an alternative. Herein, we compare three such selection strategies with the aim of identifying potent and selective inhibitors of human carbonic anhydrase II...
January 25, 2023: RSC medicinal chemistry
https://read.qxmd.com/read/36695400/allosteric-modulation-of-exosite-1-attenuates-polyphosphate-catalyzed-activation-of-factor-xi-by-thrombin
#36
JOURNAL ARTICLE
Ruiqi Yin, Vishal Patel, Rida A Malik, James C Fredenburgh, Jeffrey I Weitz
BACKGROUND: Polyphosphate (polyP) promotes feedback activation of factor (F) XI by thrombin by serving as a template. The contribution of thrombin's exosites to these interactions is unclear. OBJECTIVES: To determine the contribution of thrombin exosites 1 and 2 to polyP-induced potentiation of FXI activation by thrombin. METHODS: The affinities of α-thrombin; K109E/110E-thrombin, an exosite 1 variant, or R93E-thrombin, an exosite 2 variant; FXI; and FXIa for polyP-70 were quantified using surface plasmon resonance in the absence or presence of exosite ligands...
January 2023: Journal of Thrombosis and Haemostasis: JTH
https://read.qxmd.com/read/36653724/metalloallostery-and-transition-metal-signaling-bioinorganic-copper-chemistry-beyond-active-sites
#37
REVIEW
Vanha N Pham, Christopher J Chang
Transition metal chemistry is essential to life, where metal binding to DNA, RNA, and proteins underpins all facets of the central dogma of biology. In this context, metals in proteins are typically studied as static active site cofactors. However, the emergence of transition metal signaling, where mobile metal pools can transiently bind to biological targets beyond active sites, is expanding this conventional view of bioinorganic chemistry. This Minireview focuses on the concept of metalloallostery, using copper as a canonical example of how metals can regulate protein function by binding to remote allosteric sites (e...
January 18, 2023: Angewandte Chemie
https://read.qxmd.com/read/36642180/protein-engineering-reveals-that-gasdermin-a-preferentially-targets-mitochondrial-membranes-over-the-plasma-membrane-during-pyroptosis
#38
JOURNAL ARTICLE
Hannah C Kondolf, Dana A D'Orlando, George R Dubyak, Derek W Abbott
When activated, gasdermin family members are thought to be pore-forming proteins that cause lytic cell death. Despite this, numerous studies have suggested that the threshold for lytic cell death is dependent on which gasdermin family member is activated. Determination of the propensity of various gasdermin family members to cause pyroptosis has been handicapped by the fact that for many of them, the mechanisms and timing of their activation are uncertain. In this manuscript, we exploit the recently discovered exosite-mediated recognition of gasdermin D (GSDMD) by the inflammatory caspases to develop a system that activates gasdermin family members in an efficient and equivalent manner...
January 12, 2023: Journal of Biological Chemistry
https://read.qxmd.com/read/36580989/functional-expression-of-a-thrombin-exosite-i-inhibitor-triabin-in-escherichia-coli-and-elucidation-of-the-role-of-key-residues-in-its-inhibitory-activity
#39
JOURNAL ARTICLE
Zeyuan Mo, Zhenbang Xiao, Chunmao He
Triabin, a lipocalin-like thrombin inhibitor from the saliva of the blood-sucking triatomine bug Triatoma pallidipennis, exhibits effective inhibition comparable to hirudin despite binding exclusively at exosite I. Interestingly, it was reported that higher triabin doses would not inhibit thrombin completely, which makes it a promising antithrombotic candidate agent with a larger therapeutic window. However, few structural and functional studies about triabin have been reported in the past three decades, mostly due to the lack of a reliable and practicable recombinant expression technology for this seemingly small protein...
December 26, 2022: Biochimie
https://read.qxmd.com/read/36550107/structural-insights-into-the-covalent-regulation-of-papp-a-activity-by-prombp-and-stc2
#40
JOURNAL ARTICLE
Qihang Zhong, Honglei Chu, Guopeng Wang, Cheng Zhang, Rong Li, Fusheng Guo, Xinlu Meng, Xiaoguang Lei, Youli Zhou, Ruobing Ren, Lin Tao, Ningning Li, Ning Gao, Yuan Wei, Jie Qiao, Jing Hang
Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed by many other tissues. It cleaves insulin-like growth factor-binding proteins (IGFBPs) to increase the bioavailability of IGFs and plays essential roles in multiple growth-promoting processes. While the vast majority of the circulatory PAPP-A in pregnancy is proteolytically inactive due to covalent inhibition by proform of eosinophil major basic protein (proMBP), the activity of PAPP-A can also be covalently inhibited by another less characterized modulator, stanniocalcin-2 (STC2)...
December 22, 2022: Cell Discovery
keyword
keyword
49519
2
3
Fetch more papers »
Fetching more papers... Fetching...
Remove bar
Read by QxMD icon Read
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"

We want to hear from doctors like you!

Take a second to answer a survey question.