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453 Publications visible to you, out of a total of 453
A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity

Abstract (Expand)

ARL13B encodes for the ADP-ribosylation factor-like 13B GTPase, which is required for normal cilia structure and Sonic hedgehog (Shh) signaling. Disruptions in cilia structure or function lead to a … class of human disorders called ciliopathies. Joubert syndrome is characterized by a wide spectrum of symptoms, including a variable degree of intellectual disability, ataxia, and ocular abnormalities. Here we report a novel homozygous missense variant c.[223G>A] (p.(Gly75Arg) in the ARL13B gene, which was identified by whole-exome sequencing of a trio from a consanguineous family with multiple-affected individuals suffering from intellectual disability, ataxia, ocular defects, and epilepsy. The same variant was also identified in a second family. We saw a striking difference in the severity of ataxia between affected male and female individuals in both families. Both ARL13B and ARL13B-c.[223G>A] (p.(Gly75Arg) expression rescued the cilia length and Shh defects displayed by Arl13b hennin (null) cells, indicating that the variant did not disrupt either ARL13B function. In contrast, ARL13B-c.[223G>A] (p.(Gly75Arg) displayed a marked loss of ARL3 guanine nucleotide-exchange factor activity, with retention of its GTPase activities, highlighting the correlation between its loss of function as an ARL3 guanine nucleotide-exchange factor and Joubert syndrome.

Authors: Rafiullah Rafiullah, Alyssa B. Long, Anna A. Ivanova, Hazrat Ali, Simone Berkel, Ghulam Mustafa, Nagarajan Paramasivam, Matthias Schlesner, Stefan Wiemann, Rebecca C. Wade, Eugen Bolthauser, Martin Blum, Richard A. Kahn, Tamara Caspary, Gudrun A. Rappold

Date Published: 1st Dec 2017

Publication Type: Journal

Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery

Abstract

Not specified

Authors: Pasquale Linciano, Alice Dawson, Ina Pöhner, David M. Costa, Monica S. Sá, Anabela Cordeiro-da-Silva, Rosaria Luciani, Sheraz Gul, Gesa Witt, Bernhard Ellinger, Maria Kuzikov, Philip Gribbon, Jeanette Reinshagen, Markus Wolf, Birte Behrens, Véronique Hannaert, Paul A. M. Michels, Erika Nerini, Cecilia Pozzi, Flavio di Pisa, Giacomo Landi, Nuno Santarem, Stefania Ferrari, Puneet Saxena, Sandra Lazzari, Giuseppe Cannazza, Lucio H. Freitas-Junior, Carolina B. Moraes, Bruno S. Pascoalino, Laura M. Alcântara, Claudia P. Bertolacini, Vanessa Fontana, Ulrike Wittig, Wolfgang Müller, Rebecca C. Wade, William N. Hunter, Stefano Mangani, Luca Costantino, Maria P. Costi

Date Published: 14th Sep 2017

Publication Type: Journal

Application of a simple quantum chemical approach to ligand fragment scoring for Trypanosoma brucei pteridine reductase 1 inhibition

Abstract

Not specified

Authors: Wiktoria Jedwabny, Joanna Panecka-Hofman, Edyta Dyguda-Kazimierowicz, Rebecca C. Wade, W. Andrzej Sokalski

Date Published: 1st Aug 2017

Publication Type: Journal

TRAPP webserver: predicting protein binding site flexibility and detecting transient binding pockets.

Abstract

Not specified

Authors: Antonia Stank, Daria B. Kokh, Max Horn, Elena Sizikova, Rebecca Neil, Joanna Panecka, Stefan Richter, Rebecca C. Wade

Date Published: 3rd Jul 2017

Publication Type: Journal

Kinetics for Drug Discovery: an industry-driven effort to target drug residence time

Abstract (Expand)

A considerable number of approved drugs show non-equilibrium binding characteristics, emphasizing the potential role of drug residence times for in vivo efficacy. Therefore, a detailed understanding … of the kinetics of association and dissociation of a target–ligand complex might provide crucial insight into the molecular mechanism-of-action of a compound. This deeper understanding will help to improve decision making in drug discovery, thus leading to a better selection of interesting compounds to be profiled further. In this review, we highlight the contributions of the Kinetics for Drug Discovery (K4DD) Consortium, which targets major open questions related to binding kinetics in an industry-driven public-private partnership.

Authors: Doris A. Schuetz, Wilhelmus Egbertus Arnout de Witte, Yin Cheong Wong, Bernhard Knasmueller, Lars Richter, Daria B. Kokh, S. Kashif Sadiq, Reggie Bosma, Indira Nederpelt, Laura H. Heitman, Elena Segala, Marta Amaral, Dong Guo, Dorothee Andres, Victoria Georgi, Leigh A. Stoddart, Steve Hill, Robert M. Cooke, Chris De Graaf, Rob Leurs, Matthias Frech, Rebecca C. Wade, Elizabeth Cunera Maria de Lange, Adriaan P. IJzerman, Anke Müller-Fahrnow, Gerhard F. Ecker

Date Published: 1st Jun 2017

Publication Type: Journal

A unique profilin-actin interface is important for malaria parasite motility

Abstract (Expand)

Author summary The malaria parasite Plasmodium has two invasive forms that migrate across different tissue barriers, the ookinete and the very rapidly migrating sporozoite. Previous work has shown that … the motility of these and related parasites (e.g. Toxoplasma gondii) depends on a highly dynamic actin cytoskeleton and retrograde flow of surface adhesins. These unusual actin dynamics are due to the divergent structure of protozoan actins and the actions of actin-binding proteins, which can have non-canonical functions in these parasites. Profilin is one of the most important and most investigated actin-binding proteins, which binds ADP-actin and catalyzes ADP-ATP exchange to then promote actin polymerization. Parasite profilins bind monomeric actin and contain an additional domain compared to canonical profilins. Here we show that this additional domain of profilin is critical for actin binding and rapid sporozoite motility but has little impact on the slower ookinete. Sporozoites of a parasite line carrying mutations in this domain cannot translate force production and retrograde flow into optimal parasite motility. Using molecular dynamics simulations, we find that differences between mutant parasites in their capacity to migrate can be traced back to a single hydrogen bond at the actin-profilin interface.

Authors: Catherine A. Moreau, Saligram P. Bhargav, Hirdesh Kumar, Katharina A. Quadt, Henni Piirainen, Léanne Strauss, Jessica Kehrer, Martin Streichfuss, Joachim P. Spatz, Rebecca C. Wade, Inari Kursula, Friedrich Frischknecht

Date Published: 26th May 2017

Publication Type: Journal

Evolution of an intricate J-protein network driving protein disaggregation in eukaryotes.

Abstract

Not specified

Authors: Nadinath B Nillegoda, Antonia Stank, Duccio Malinverni, Niels Alberts, Anna Szlachcic, Alessandro Barducci, Paolo De Los Rios, Rebecca C Wade, Bernd Bukau

Date Published: 15th May 2017

Publication Type: Journal

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