All Outputs (28)

Epithelial Interleukin‐1 Receptor‐Like‐1 Activation Is Contingent on Interleukin‐33 Isoforms and Asthma‐Related Receptor Variation (2024)
Journal Article
Portelli, M., Ketelaar, M., Bates, S., Csomor, E., Shaw, D., Emsley, J., Brightling, C., Hall, I., Affleck, K., Edwards, M., Nawijn, M., Koppelman, G., Van Oosterhout, A., & Sayers, I. (2024). Epithelial Interleukin‐1 Receptor‐Like‐1 Activation Is Contingent on Interleukin‐33 Isoforms and Asthma‐Related Receptor Variation. Clinical and Experimental Allergy, https://doi.org/10.1111/cea.14562

Introduction: The interleukin-33/interleukin-1 receptor-like-1 (IL-33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants'... Read More about Epithelial Interleukin‐1 Receptor‐Like‐1 Activation Is Contingent on Interleukin‐33 Isoforms and Asthma‐Related Receptor Variation.

Aptamer BT200 blocks interaction of K1405-1408 in the VWF-A1 domain with macrophage LRP1 (2024)
Journal Article
Chan Kwo Chion, A., Byrne, C., Atiq, F., Doherty, D., Aguila, S., Fazavana, J., Lopes, P., Karampini, E., Amin, A., Preston, R. J., Baker, R. I., McKinnon, T. A., Zhu, S., Gilbert, J. C., Emsley, J., Jilma, B., & O'Donnell, J. S. (2024). Aptamer BT200 blocks interaction of K1405-1408 in the VWF-A1 domain with macrophage LRP1. Blood, 144(13), 1445-1456. https://doi.org/10.1182/blood.2024024055

Rondaptivan pegol (previously BT200) is a PEGylated RNA aptamer that binds to the A1 domain of VWF. Recent clinical trials demonstrated that BT200 significantly increased plasma VWF-FVIII levels by attenuating VWF clearance. The biological mechanism(... Read More about Aptamer BT200 blocks interaction of K1405-1408 in the VWF-A1 domain with macrophage LRP1.

Discovery of α-Amidobenzylboronates as Highly Potent Covalent Inhibitors of Plasma Kallikrein (2024)
Journal Article
Allison, M., Davie, R. L., Mogg, A. J., Hampton, S. L., Emsley, J., & Stocks, M. J. (2024). Discovery of α-Amidobenzylboronates as Highly Potent Covalent Inhibitors of Plasma Kallikrein. ACS Medicinal Chemistry Letters, 15(4), 501–509. https://doi.org/10.1021/acsmedchemlett.3c00572

Hereditary angioedema (HAE), a rare genetic disorder, is associated with uncontrolled plasma kallikrein (PKa) enzyme activity leading to the generation of bradykinin swelling in subcutaneous and submucosal membranes in various locations of the body.... Read More about Discovery of α-Amidobenzylboronates as Highly Potent Covalent Inhibitors of Plasma Kallikrein.

Conformational activation and inhibition of von Willebrand factor by targeting its autoinhibitory module (2024)
Journal Article
Arce, N. A., Markham-Lee, Z., Liang, Q., Najmudin, S., Legan, E. R., Dean, G., …Li, R. (2024). Conformational activation and inhibition of von Willebrand factor by targeting its autoinhibitory module. Blood, 143(19), 1992-2004. https://doi.org/10.1182/blood.2023022038

Activation of von Willebrand factor (VWF) is a tightly controlled process governed primarily by local elements around its A1 domain. Recent studies suggest that the O-glycosylated sequences flanking the A1 domain constitute a discontinuous and force-... Read More about Conformational activation and inhibition of von Willebrand factor by targeting its autoinhibitory module.

Design, Synthesis, and Evaluation of New 1H-Benzo[d]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections (2024)
Journal Article
Soukarieh, F., Mashabi, A., Richardson, W., Oton, E. V., Romero, M., Dubern, J., …Cámara, M. (2024). Design, Synthesis, and Evaluation of New 1H-Benzo[d]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections. Journal of Medicinal Chemistry, 67(2), 1008-1023. https://doi.org/10.1021/acs.jmedchem.3c00973

Pseudomonas aeruginosa is one of the top priority pathogens that requires immediate attention according to the World Health Organisation (WHO). Due to the alarming shortage of novel antimicrobials, targeting quorum sensing (QS), a bacterial cell to c... Read More about Design, Synthesis, and Evaluation of New 1H-Benzo[d]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections.

High molecular weight kininogen interactions with the homologs prekallikrein and factor XI: importance to surface-induced coagulation (2023)
Journal Article
Mohammed, B. M., Sun, M., Cheng, Q., Litvak, M., McCrae, K. R., Emsley, J., …Gailani, D. (2024). High molecular weight kininogen interactions with the homologs prekallikrein and factor XI: importance to surface-induced coagulation. Journal of Thrombosis and Haemostasis, 22(1), 225-237. https://doi.org/10.1016/j.jtha.2023.09.027

Background: In plasma, high molecular weight kininogen (HK) is either free or bound to prekallikrein (PK) or factor (F) XI (FXI). During contact activation, HK is thought to anchor PK and FXI to surfaces, facilitating their conversion to the protease... Read More about High molecular weight kininogen interactions with the homologs prekallikrein and factor XI: importance to surface-induced coagulation.

Conformational analysis and interaction of the Staphylococcus aureus transmembrane peptidase AgrB with its AgrD propeptide substrate (2023)
Journal Article
Bardelang, P., Murray, E. J., Blower, I., Zandomeneghi, S., Goode, A., Hussain, R., …Bonev, B. B. (2023). Conformational analysis and interaction of the Staphylococcus aureus transmembrane peptidase AgrB with its AgrD propeptide substrate. Frontiers in Chemistry, 11, Article 1113885. https://doi.org/10.3389/fchem.2023.1113885

Virulence gene expression in the human pathogen, S. aureus is regulated by the agr (accessory gene regulator) quorum sensing (QS) system which is conserved in diverse Gram-positive bacteria. The agr QS signal molecule is an autoinducing peptide (AIP)... Read More about Conformational analysis and interaction of the Staphylococcus aureus transmembrane peptidase AgrB with its AgrD propeptide substrate.

Structures of factor XI and prekallikrein bound to domain 6 of high–molecular weight kininogen reveal alternate domain 6 conformations and exosites (2023)
Journal Article
Li, C., Barroeta, A. B., Wong, S. S., Kim, H. J., Pathak, M., Dreveny, I., …Emsley, J. (2023). Structures of factor XI and prekallikrein bound to domain 6 of high–molecular weight kininogen reveal alternate domain 6 conformations and exosites. Journal of Thrombosis and Haemostasis, https://doi.org/10.1016/j.jtha.2023.03.042

Background: High–molecular weight kininogen (HK) circulates in plasma as a complex with zymogen prekallikrein (PK). HK is both a substrate and a cofactor for activated plasma kallikrein, and the principal exosite interactions occur between PK N-termi... Read More about Structures of factor XI and prekallikrein bound to domain 6 of high–molecular weight kininogen reveal alternate domain 6 conformations and exosites.

Characterizing the binding of glycoprotein VI with nanobody 35 reveals a novel monomeric structure of glycoprotein VI where the conformation of D1+D2 is independent of dimerization (2022)
Journal Article
Damaskinaki, F. N., Jooss, N. J., Martin, E. M., Clark, J. C., Thomas, M. R., Poulter, N. S., …Slater, A. (2023). Characterizing the binding of glycoprotein VI with nanobody 35 reveals a novel monomeric structure of glycoprotein VI where the conformation of D1+D2 is independent of dimerization. Journal of Thrombosis and Haemostasis, 21(2), 317-328. https://doi.org/10.1016/j.jtha.2022.11.002

Background: The platelet–signaling receptor glycoprotein VI (GPVI) is a promising antithrombotic target. We have previously raised a series of high-affinity nanobodies (Nbs) against GPVI and identified Nb2, Nb21, and Nb35 as potent GPVI inhibitors. T... Read More about Characterizing the binding of glycoprotein VI with nanobody 35 reveals a novel monomeric structure of glycoprotein VI where the conformation of D1+D2 is independent of dimerization.

Design and Evaluation of New Quinazolin-4(3 H)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa (2021)
Journal Article
Soukarieh, F., Mashabi, A., Richardson, W., Oton, E. V., Romero, M., Roberston, S. N., …Cámara, M. (2021). Design and Evaluation of New Quinazolin-4(3 H)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa. ACS Infectious Diseases, 7(9), 2666-2685. https://doi.org/10.1021/acsinfecdis.1c00175

P. aeruginosa (PA) continues to pose a threat to global public health due to its high levels of antimicrobial resistance (AMR). The ongoing AMR crisis has led to an alarming shortage of effective treatments for resistant microbes, and hence there is... Read More about Design and Evaluation of New Quinazolin-4(3 H)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa.

Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR (2020)
Journal Article
Grossman, S., Soukarieh, F., Richardson, W., Liu, R., Mashabi, A., Emsley, J., …Stocks, M. J. (2020). Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR. European Journal of Medicinal Chemistry, 208, Article 112778. https://doi.org/10.1016/j.ejmech.2020.112778

© 2020 The Authors Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is v... Read More about Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR.

Factor XII and kininogen asymmetric assembly with gC1qR/C1QBP/P32 is governed by allostery (2020)
Journal Article
Kaira, B. G., Slater, A., McCrae, K. R., Dreveny, I., Sumya, U.-M., Mutch, N. J., …Emsley, J. (2020). Factor XII and kininogen asymmetric assembly with gC1qR/C1QBP/P32 is governed by allostery. Blood, 136(14), 1685–1697. https://doi.org/10.1182/blood.2020004818

The contact system is composed of Factor XII (FXII), prekallikrein (PK) and co-factor kininogen (HK). The globular C1q receptor (gC1qR) has been shown to interact with FXII and HK. We reveal the FXII fibronectin type II domain (FnII) binds gC1qR in a... Read More about Factor XII and kininogen asymmetric assembly with gC1qR/C1QBP/P32 is governed by allostery.

Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa (2020)
Journal Article
Soukarieh, F., Liu, R., Romero, M., Roberston, S. N., Richardson, W., Lucanto, S., …Stocks, M. J. (2020). Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa. Frontiers in Chemistry, 8, Article 204. https://doi.org/10.3389/fchem.2020.00204

© Copyright © 2020 Soukarieh, Liu, Romero, Roberston, Richardson, Lucanto, Oton, Qudus, Mashabi, Grossman, Ali, Sou, Kukavica-Ibrulj, Levesque, Bergström, Halliday, Mistry, Emsley, Heeb, Williams, Cámara and Stocks. Current treatments for Pseudomonas... Read More about Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa.

Crystal structure and substrate-induced activation of ADAMTS13 (2019)
Journal Article
Petri, A., Kim, H. J., Xu, Y., de Groot, R., Li, C., Vandenbulcke, A., …Crawley, J. T. (2019). Crystal structure and substrate-induced activation of ADAMTS13. Nature Communications, 10, Article 3781. https://doi.org/10.1038/s41467-019-11474-5

Platelet recruitment to sites of blood vessel damage is highly dependent upon von Willebrand factor (VWF). VWF platelet-tethering function is proteolytically regulated by the metalloprotease ADAMTS13. Proteolysis depends upon shear-induced conformati... Read More about Crystal structure and substrate-induced activation of ADAMTS13.

Crystal structures of the recombinant β-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics (2019)
Journal Article
Pathak, M., Manna, R., Li, C., Kaira, B. G., Hamad, B. K., Belviso, B. D., …Emsley, J. (2019). Crystal structures of the recombinant β-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics. Acta Crystallographica. Section d, Structural Biology, 75(6), 578-591. https://doi.org/10.1107/s2059798319006910

© 2019 International Union of Crystallography. Coagulation factor XII (FXII) is a key initiator of the contact pathway, which contributes to inflammatory pathways. FXII circulates as a zymogen, which when auto-activated forms factor XIIa (FXIIa). Her... Read More about Crystal structures of the recombinant β-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics.

Structural basis of the leukocyte integrin Mac-1 I-domain interactions with the platelet glycoprotein Ib (2019)
Journal Article
Morgan, J., Saleem, M., Ng, R., Armstrong, C., Wong, S. S., Caulton, S. G., …Emsley, J. (2019). Structural basis of the leukocyte integrin Mac-1 I-domain interactions with the platelet glycoprotein Ib. Blood Advances, 3(9), 1450-1459. https://doi.org/10.1182/bloodadvances.2018027011

Cell-surface receptor interactions between leukocyte integrin macrophage-1 antigen (Mac-1, also known as CR3, aMb2, CD11b/CD18) and platelet glycoprotein Iba (GPIba) are critical to vascular inflammation. To define the key residues at the binding inter... Read More about Structural basis of the leukocyte integrin Mac-1 I-domain interactions with the platelet glycoprotein Ib.

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI (2019)
Journal Article
Li, C., Voos, K. M., Pathak, M., Hall, G., McCrae, K. R., Dreveny, I., …Emsley, J. (2019). Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI. Journal of Thrombosis and Haemostasis, 17(5), 759-770. https://doi.org/10.1111/jth.14418

Background
Plasma prekallikrein (PK) and factor XI (FXI) are apple domain‐containing serine proteases that when activated to PKa and FXIa cleave substrates kininogen, factor XII, and factor IX, respectively, directing plasma coagulation, bradykinin... Read More about Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI.

The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel (2018)
Journal Article
Ward, S. J., Gratton, H. E., Indrayudha, P., Michavila, C., Mukhopadhyay, R., Maurer, S. K., …Dreveny, I. (2018). The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel. Journal of Biological Chemistry, 293(45), 17362-17374. https://doi.org/10.1074/jbc.RA118.003857

© 2018 Ward et al. Ubiquitin-specific protease 15 (USP15) regulates important cellular processes, including transforming growth factor β (TGF-β) signaling, mitophagy, mRNA processing, and innate immune responses; however, structural information on US... Read More about The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel.

Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation (2017)
Journal Article
Hamad, B. K., Pathak, M., Manna, R., Fischer, P. M., Emsley, J., & Dekker, L. V. (2017). Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation. Journal of Thrombosis and Haemostasis, 15(9), 1818-1828. https://doi.org/10.1111/jth.13773

Background: Corn trypsin inhibitor (CTI) has selectivity for serine proteases coagulation factor XII (FXII) and trypsin. CTI is in widespread use as a reagent that specifically inhibits the intrinsic pathway of blood coagulation but not the extrinsic... Read More about Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation.

Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation (2017)
Journal Article
Ivanov, I., Matafonov, A., Sun, M., Cheng, Q., Dickeson, S. K., Verhamme, I. M., …Gailani, D. (2017). Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation. Blood, 129(11), 1527-1537. https://doi.org/10.1182/blood-2016-10-744110

When blood is exposed to variety of artificial surfaces and biologic substances, the plasma proteins factor XII (FXII) and prekallikrein undergo reciprocal proteolytic conversion to the proteases αFXIIa and α-kallikrein by a process called contact ac... Read More about Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation.