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Instruments / Technical Area	Publication Details	Published	Actions
I04-Macromolecular Crystallography	Fragment-based computational design of antibodies targeting structured epitopes Mauricio Aguilar Rangel , Alice Bedwell , Elisa Costanzi , Ross J. Taylor , Rosaria Russo , Gonçalo J. L. Bernardes , Stefano Ricagno , Judith Frydman , Michele Vendruscolo , Pietro Sormanni Science Advances 8 DOI: 10.1126/sciadv.abp9540 Diamond Proposal Number(s): [20221] Open Access Show Abstract ▼ Abstract: De novo design methods hold the promise of reducing the time and cost of antibody discovery while enabling the facile and precise targeting of predetermined epitopes. Here, we describe a fragment-based method for the combinatorial design of antibody binding loops and their grafting onto antibody scaffolds. We designed and tested six single-domain antibodies targeting different epitopes on three antigens, including the receptor-binding domain of the SARS-CoV-2 spike protein. Biophysical characterization showed that all designs are stable and bind their intended targets with affinities in the nanomolar range without in vitro affinity maturation. We further discuss how a high-resolution input antigen structure is not required, as similar predictions are obtained when the input is a crystal structure or a computer-generated model. This computational procedure, which readily runs on a laptop, provides a starting point for the rapid generation of lead antibodies binding to preselected epitopes.	Nov 2022
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Two novel fish paralogs provide insights into the Rid family of imine deaminases active in pre-empting enamine/imine metabolic damage Stefania Digiovanni , Cristina Visentin , Genny Degani , Alberto Barbiroli , Matteo Chiara , Luca Regazzoni , Flavio Di Pisa , Andrew J. Borchert , Diana M. Downs , Stefano Ricagno , Maria Antonietta Vanoni , Laura Popolo Scientific Reports 10 DOI: 10.1038/s41598-020-66663-w Diamond Proposal Number(s): [20221] Open Access Show Abstract ▼ Abstract: Reactive Intermediate Deaminase (Rid) protein superfamily includes eight families among which the RidA is conserved in all domains of life. RidA proteins accelerate the deamination of the reactive 2-aminoacrylate (2AA), an enamine produced by some pyridoxal phosphate (PLP)-dependent enzymes. 2AA accumulation inhibits target enzymes with a detrimental impact on fitness. As a consequence of whole genome duplication, teleost fish have two ridA paralogs, while other extant vertebrates contain a single-copy gene. We investigated the biochemical properties of the products of two paralogs, identified in Salmo salar. SsRidA-1 and SsRidA-2 complemented the growth defect of a Salmonella enterica ridA mutant, an in vivo model of 2AA stress. In vitro, both proteins hydrolyzed 2-imino acids (IA) to keto-acids and ammonia. SsRidA-1 was active on IA derived from nonpolar amino acids and poorly active or inactive on IA derived from other amino acids tested. In contrast, SsRidA-2 had a generally low catalytic efficiency, but showed a relatively higher activity with IA derived from L-Glu and aromatic amino acids. The crystal structures of SsRidA-1 and SsRidA-2 provided hints of the remarkably different conformational stability and substrate specificity. Overall, SsRidA-1 is similar to the mammalian orthologs whereas SsRidA-2 displays unique properties likely generated by functional specialization of a duplicated ancestral gene.	Jun 2020

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