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Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Crystal structure of peptide‐bound neprilysin reveals key binding interactions Stephen Moss , Vasanta Subramanian , K. Ravi Acharya Febs Letters 46 DOI: 10.1002/1873-3468.13602 Diamond Proposal Number(s): [17212] Show Abstract ▼ Abstract: Neprilysin (NEP) is a promiscuous zinc metalloprotease with broad substrate specificity and cleaves a remarkable diversity of substrates through endopeptidase action. Two of these – amyloid‐β and natriuretic peptides – implicate the enzyme in both Alzheimer’s disease and cardiovascular disease, respectively. Here, we report the creation of a catalytically inactive NEP (E584D) to determine the first peptide‐bound crystal structure at 2.6 Å resolution. The structure reveals key interactions involved in substrate binding which we have identified to be conserved in other known zinc metalloproteases. In addition, the structure provides evidence for a potential exosite within the central cavity that may play a critical role in substrate positioning. Together, these results contribute to our understanding of the molecular function of NEP.	Sep 2019
I03-Macromolecular Crystallography	High resolution crystal structure of substrate-free human neprilysin Stephen Moss , Vasanta Subramanian , K. Ravi Acharya Journal Of Structural Biology DOI: 10.1016/j.jsb.2018.06.004 Diamond Proposal Number(s): [17212] Show Abstract ▼ Abstract: Neprilysin is a transmembrane M13 zinc metalloprotease responsible for the degradation of several biologically active peptides including insulin, enkephalin, substance P, bradykinin, endothelin-1, neurotensin and amyloid-β. The protein has received attention for its role in modulating blood pressure responses with its inhibition producing an antihypertensive response. To date, several inhibitor bound crystal structures of the human neprilysin extracellular domain have been determined, but, a structure free of bound inhibitor or substrate has yet to be reported. Here, we report the first crystal structure free of substrate or inhibitor for the extracellular catalytic domain of human neprilysin at 1.9 Å resolution. This structure will provide a reference point for comparisons to future inhibitor or substrate bound structures. The neprilysin structure also reveals that a closed protein conformation can be adopted in protein crystals absent of bound substrate or inhibitor.	Jun 2018
I04-Macromolecular Crystallography	The novel DNA binding mechanism of ridinilazole, a precision Clostridiodes difficile antibiotic Clive S. Mason , Tim Avis , Chenlin Hu , Nabeetha Nagalingam , Manikhandan Mudaliar , Chris Coward , Khurshida Begum , Kathleen Gajewski , M. Jahangir Alam , Eugenie Bassères , Stephen Moss , Stefanie Reich , Esther Duperchy , Keith R. Fox , Kevin W. Garey , David J. Powell Antimicrobial Agents And Chemotherapy DOI: 10.1128/aac.01563-22 Open Access Show Abstract ▼ Abstract: Clostridioides difficile infection (CDI) causes substantial morbidity and mortality worldwide with limited antibiotic treatment options. Ridinilazole is a precision bisbenzimidazole antibiotic being developed to treat CDI and reduce unacceptably high rates of infection recurrence in patients. Although in late clinical development, the precise mechanism of action by which ridinilazole elicits its bactericidal activity has remained elusive. Here, we present conclusive biochemical and structural data to demonstrate that ridinilazole has a primary DNA binding mechanism, with a co-complex structure confirming binding to the DNA minor groove. Additional RNA-seq data indicated early pleiotropic changes to transcription, with broad effects on multiple C. difficile compartments and significant effects on energy generation pathways particularly. DNA binding and genomic localization was confirmed through confocal microscopy utilizing the intrinsic fluorescence of ridinilazole upon DNA binding. As such, ridinilazole has the potential to be the first antibiotic approved with a DNA minor groove binding mechanism of action.	Apr 2023

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