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Instruments / Technical Area	Publication Details	Published	Actions
B21-High Throughput SAXS	Structural and hydrodynamic characterization of dimeric human oligoadenylate synthetase 2 Amit Koul , Darren Gemmill , Nikhat Lubna , Markus Meier , Natalie Krahn , Evan P. Booy , Jörg Stetefeld , Trushar R. Patel , Sean A. Mckenna Biophysical Journal DOI: 10.1016/j.bpj.2020.04.025 Diamond Proposal Number(s): [16028, 22113] Open Access Show Abstract ▼ Abstract: Oligoadenylate synthetases (OASs) are a family of interferon-inducible enzymes that require double-stranded RNA (dsRNA) as a cofactor. Upon binding dsRNA, OAS undergoes a conformational change and is activated to polymerize ATP into 2′-5′-oligoadenylate chains. The OAS family consists of several isozymes, with unique domain organizations to potentially interact with dsRNA of variable length, providing diversity in viral RNA recognition. In addition, oligomerization of OAS isozymes, potentially OAS1 and OAS2, is hypothesized to be important for 2′-5′-oligoadenylate chain building. In this study, we present the solution conformation of dimeric human OAS2 using an integrated approach involving small-angle x-ray scattering, analytical ultracentrifugation, and dynamic light scattering techniques. We also demonstrate OAS2 dimerization using immunoprecipitation approaches in human cells. Whereas mutation of a key active-site aspartic acid residue prevents OAS2 activity, a C-terminal mutation previously hypothesized to disrupt OAS self-association had only a minor effect on OAS2 activity. Finally, we also present the solution structure of OAS1 monomer and dimer, comparing their hydrodynamic properties with OAS2. In summary, our work presents the first, to our knowledge, dimeric structural models of OAS2 that enhance our understanding of the oligomerization and catalytic function of OAS enzymes.	May 2020
I03-Macromolecular Crystallography	Design, synthesis, and biological evaluation of novel indoles targeting the influenza PB2 cap binding region David Craig Mcgowan , Wendy Balemans , Werner Embrechts , Magali Motte , Jeremy Keown , Christophe Buyck , Jordi Corbera , Mario Funes , Laura Moreno , Ludwig Cooymans , Abdellah Tahri , Julien Eymard , Bart Stoops , Rudy Strijbos , Joke Van Den Berg , Ervin Fodor , Jonathan Grimes , Anil Koul , Tim H. M. Jonckers , Pierre Raboisson , Jerome Guillemont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01091 Diamond Proposal Number(s): [14744] Show Abstract ▼ Abstract: In the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements for the 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, a 5,7-difluoroindole derivative 11a was identified as a potent and metabolically stable influenza inhibitor. 11a demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that 11a was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of 11a bound to influenza A PB2 cap region is disclosed here and deposited to the PDB.	Oct 2019

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