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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome Alexander T. Baker , Ryan J. Boyd , Daipayan Sarkar , Alicia Teijeira-Crespo , Chun Kit Chan , Emily Bates , Kasim Waraich , John Vant , Eric Wilson , Chloe D. Truong , Magdalena Lipka-Lloyd , Petra Fromme , Josh Vermaas , Dewight Williams , Leeann Machiesky , Meike Heurich , Bolni M. Nagalo , Lynda Coughlan , Scott Umlauf , Po-Lin Chiu , Pierre J. Rizkallah , Taylor S. Cohen , Alan L. Parker , Abhishek Singharoy , Mitesh J. Borad Science Advances 7 DOI: 10.1126/sciadv.abl8213 Diamond Proposal Number(s): [20147] Open Access Show Abstract ▼ Abstract: Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstrates that all three adenoviruses deployed as vaccination vectors versus SARS-CoV-2 bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT. We have determined the structure of the ChAdOx1 viral vector and used it in state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism with PF4, which was confirmed experimentally by surface plasmon resonance. These data confirm that PF4 is capable of forming stable complexes with clinically relevant adenoviruses, an important step in unraveling the mechanisms underlying TTS.	Dec 2021
I04-Macromolecular Crystallography	Diversity within the adenovirus fiber knob hypervariable loops influences primary receptor interactions Alexander T. Baker , Alexander Greenshields Watson , Lynda Coughlan , James A. Davies , Hanni Uusi-Kerttula , David K. Cole , Pierre J. Rizkallah , Alan L. Parker Nature Communications 10 DOI: 10.1038/s41467-019-08599-y Diamond Proposal Number(s): [14843] Open Access Show Abstract ▼ Abstract: Adenovirus based vectors are of increasing importance for wide ranging therapeutic applications. As vaccines, vectors derived from human adenovirus species D serotypes 26 and 48 (HAdV-D26/48) are demonstrating promising efficacy as protective platforms against infectious diseases. Significant clinical progress has been made, yet definitive studies underpinning mechanisms of entry, infection, and receptor usage are currently lacking. Here, we perform structural and biological analysis of the receptor binding fiber-knob protein of HAdV-D26/48, reporting crystal structures, and modelling putative interactions with two previously suggested attachment receptors, CD46 and Coxsackie and Adenovirus Receptor (CAR). We provide evidence of a low affinity interaction with CAR, with modelling suggesting affinity is attenuated through extended, semi-flexible loop structures, providing steric hindrance. Conversely, in silico and in vitro experiments are unable to provide evidence of interaction between HAdV-D26/48 fiber-knob with CD46, or with Desmoglein 2. Our findings provide insight into the cell-virus interactions of HAdV-D26/48, with important implications for the design and engineering of optimised Ad-based therapeutics.	Feb 2019

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