| 1. |
- Bu, Guanhong, et al.
(author)
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Simeprevir: The First Macrocyclic Drug Elucidated Ab Initio by MicroED
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Other publication (other academic/artistic)abstract
- Obtaining single crystal X-ray driffraction (XRD) structures of macrocylcic drugs has proven to be challenging. One of the major bottlenecks is growing sufficiently large crystals needed for XRD. MicroED is capable of solving structures from sub-micrometer. This communication descrribes the first MicroED structure of the macrocyclic drug simeprevir.
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| 2. |
- Danelius, Emma, et al.
(author)
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MicroED as a Powerful Tool for Structure Determination of Macrocyclic Drug Compounds Directly from Their Powder Formulations
- 2023
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In: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 18:12, s. 2582-2589
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Journal article (peer-reviewed)abstract
- Macrocycles are important drug leads with many advantages including the ability to target flat and featureless binding sites as well as to act as molecular chameleons and thereby reach intracellular targets. However, due to their complex structures and inherent flexibility, macrocycles are difficult to study structurally, and there are limited structural data available. Herein, we use the cryo-EM method MicroED to determine the novel atomic structures of several macrocycles that have previously resisted structural determination. We show that structures of similar complexity can now be obtained rapidly from nanograms of material and that different conformations of flexible compounds can be derived from the same experiment. These results will have an impact on contemporary drug discovery as well as natural product exploration.
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| 3. |
- King, Neil P., et al.
(author)
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Computational Design of Self-Assembling Protein Nanomaterials with Atomic Level Accuracy
- 2012
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In: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 336:6085, s. 1171-1174
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Journal article (peer-reviewed)abstract
- We describe a general computational method for designing proteins that self-assemble to a desired symmetric architecture. Protein building blocks are docked together symmetrically to identify complementary packing arrangements, and low-energy protein-protein interfaces are then designed between the building blocks in order to drive self-assembly. We used trimeric protein building blocks to design a 24-subunit, 13-nm diameter complex with octahedral symmetry and a 12-subunit, 11-nm diameter complex with tetrahedral symmetry. The designed proteins assembled to the desired oligomeric states in solution, and the crystal structures of the complexes revealed that the resulting materials closely match the design models. The method can be used to design a wide variety of self-assembling protein nanomaterials.
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| 4. |
- Krotee, Pascal, et al.
(author)
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Atomic structures of fibrillar segments of hIAPP suggest tightly mated beta-sheets are important or cytotoxicity
- 2017
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In: eLIFE. - 2050-084X. ; 6
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Journal article (peer-reviewed)abstract
- hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic beta-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of beta-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile beta-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP.
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| 5. |
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| 6. |
- Meyer, Peter A., et al.
(author)
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Data publication with the structural biology data grid supports live analysis
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models and indispensable for development of structural biology processing methods. Here, we established a diffraction data publication and dissemination system, Structural Biology Data Grid (SBDG; data. sbgrid. org), to preserve primary experimental data sets that support scientific publications. Data sets are accessible to researchers through a community driven data grid, which facilitates global data access. Our analysis of a pilot collection of crystallographic data sets demonstrates that the information archived by SBDG is sufficient to reprocess data to statistics that meet or exceed the quality of the original published structures. SBDG has extended its services to the entire community and is used to develop support for other types of biomedical data sets. It is anticipated that access to the experimental data sets will enhance the paradigm shift in the community towards a much more dynamic body of continuously improving data analysis.
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