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Crystallographic fragment screening supports tool compound discovery and reveals conformational flexibility in human deoxyhypusine synthase
No full textDeoxyhypusine synthase (DHS) catalyzes the rate-limiting step of hypusination, a unique post-translational modification of eukaryotic translation factor 5 A (eIF5A). While DHS activity plays a critical role in both normal cellular processes and disease development, the lack of specific molecular tools has hindered detailed studies of this enzyme and the hypusination pathway in general. Existing inhibitors, such as polyamine analogs, suffer from limited specificity and versatility. In this study, we utilized crystallographic fragment screening (CFS) to identify potential DHS inhibitors and explore novel applications of this approach. With an unprecedented hit rate of 39%, we identified fragment clusters binding at key sites, including the active site entrance, the tetramer interface, the regulatory ball-and-chain motif, and potentially allosteric regions on the enzyme’s surface. Notably, we discovered a covalent modifier that targets the catalytic lysine residue in an oxidoreductase reaction-specific manner, as well as fragments that induce significant structural rearrangements of crucial regulatory elements. Our findings establish a framework for extending CFS beyond traditional inhibitor discovery, demonstrating its utility in probing protein dynamics, identifying novel binding pockets, and investigating regulatory mechanisms. These results offer new insights into DHS function, hypusination dynamics, and the broader methodological advancements that CFS contributes to structural biology and protein regulation research
Obesity‐related distress and obesity burnout : towards a conceptual framework for disease‐specific emotional burden in obesity
No full textSuccessful use of the occlusion balloon as a bridge to surgery for subclavian vein rupture during transvenous lead extraction
No full textImportance of biocrusts for restoring ecosystem functions in two contrasting habitats of former sand mines
No full textInherited thrombophilia as a risk factor for persistent left ventricular thrombus following acute myocardial infarction
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Emerging varieties of resilience : experiences from Germany, Poland and Ukraine
No full textThis book focuses on developments of resilience in Europe, discussing its different interpretations and enactments, as well as approaches to national security and crisis and disaster management.
Examining war-time resilience, increased refugee flows into the EU, societal resilience, and its general application of the concept in national security strategies, the book juxtaposes the multifaceted nature of resilience in different, yet connected, European countries. In doing so, it illuminates the multiplicity of approaches and interpretations that allows a deeper understanding of dynamically (re)developing approaches to resilience.
This book will be of key interest to scholars, students, and practitioners working in crisis response, disaster management, and resilience and more broadly to European studies, migration studies, security studies, politics, public policy, and international relations