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Instruments / Technical Area	Publication Details	Published	Actions
B21-High Throughput SAXS I03-Macromolecular Crystallography	Periscope Proteins are variable-length regulators of bacterial cell surface interactions Fiona Whelan , Aleix Lafita , James Gilburt , Clement Degut , Samuel C. Griffiths , Huw Jenkins , Alexander N. St John , Emanuele Paci , James W. B. Moir , Michael J. Plevin , Christoph G. Baumann , Alex Bateman , Jennifer R. Potts Proceedings Of The National Academy Of Sciences 118 DOI: 10.1073/pnas.2101349118 Diamond Proposal Number(s): [9948] Open Access Show Abstract ▼ Abstract: Changes at the cell surface enable bacteria to survive in dynamic environments, such as diverse niches of the human host. Here, we reveal “Periscope Proteins” as a widespread mechanism of bacterial surface alteration mediated through protein length variation. Tandem arrays of highly similar folded domains can form an elongated rod-like structure; thus, variation in the number of domains determines how far an N-terminal host ligand binding domain projects from the cell surface. Supported by newly available long-read genome sequencing data, we propose that this class could contain over 50 distinct proteins, including those implicated in host colonization and biofilm formation by human pathogens. In large multidomain proteins, sequence divergence between adjacent domains appears to reduce interdomain misfolding. Periscope Proteins break this “rule,” suggesting that their length variability plays an important role in regulating bacterial interactions with host surfaces, other bacteria, and the immune system.	Jun 2021
I04-Macromolecular Crystallography	High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity Wen Zhu , Ashish Radadiya , Claudine Bisson , Sabine Wenzel , Brian E. Nordin , Francisco Martínez-Márquez , Tsuyoshi Imasaki , Svetlana E. Sedelnikova , Adriana Coricello , Patrick Baumann , Alexandria H. Berry , Tyzoon K. Nomanbhoy , John W. Kozarich , Yi Jin , David W. Rice , Yuichiro Takagi , Nigel G. J. Richards Communications Biology 2 DOI: 10.1038/s42003-019-0587-z Diamond Proposal Number(s): [12788] Open Access Show Abstract ▼ Abstract: Expression of human asparagine synthetase (ASNS) promotes metastatic progression and tumor cell invasiveness in colorectal and breast cancer, presumably by altering cellular levels of L-asparagine. Human ASNS is therefore emerging as a bona fide drug target for cancer therapy. Here we show that a slow-onset, tight binding inhibitor, which exhibits nanomolar affinity for human ASNS in vitro, exhibits excellent selectivity at 10 μM concentration in HCT-116 cell lysates with almost no off-target binding. The high-resolution (1.85 Å) crystal structure of human ASNS has enabled us to identify a cluster of negatively charged side chains in the synthetase domain that plays a key role in inhibitor binding. Comparing this structure with those of evolutionarily related AMP-forming enzymes provides insights into intermolecular interactions that give rise to the observed binding selectivity. Our findings demonstrate the feasibility of developing second generation human ASNS inhibitors as lead compounds for the discovery of drugs against metastasis.	Sep 2019

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