Electron diffraction determines molecular absolute configuration in a pharmaceutical nanocrystal

Brázda, Petr; Palatinus, Lukáš; Babor, Martin

doi:10.1126/science.aaw2560

Cited by 168 publications

(176 citation statements)

References 39 publications

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“…Continuous‐rotation 3D‐ED, also referred to as MicroED, has been proven to be extremely efficient for the structure determination of pharmaceuticals without the need of growing large crystals . However, to our knowledge, all pharmaceuticals solved so far, beside the co‐crystal sofosbuvir/ l ‐proline, were test samples whose structure had already been previously solved by X‐ray diffraction. Orthocetamol (2‐acetamidophenol) is an ortho ‐substituted regioisomer of paracetamol (4‐acetamidophenol), one of the most widely used pharmaceuticals in the world (Figure S1, Supporting Information).…”

Section: Figuresupporting

confidence: 62%

The Crystal Structure of Orthocetamol Solved by 3D Electron Diffraction

et al. 2019

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Section: Figuresupporting

confidence: 62%

The Crystal Structure of Orthocetamol Solved by 3D Electron Diffraction

et al. 2019

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“…While this has not been performed in the present work, it may prove beneficial for cases where clear boundaries of adjacent crystals are not readily discernible, or to study and exploit local lattice structures 46,68 .…”

Section: Crystal Finding and Acquisition Programmingmentioning

confidence: 99%

Serial protein crystallography in an electron microscope

Bücker

Hogan-Lamarre

Mehrabi

et al. 2019

Preprint

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1 Sentence summary: Serial diffraction (SerialED) enables high-throughput, low dose protein crystallography from sub-micron crystals using conventional S/TEM microscopes. AbstractWe describe a new method for serial electron diffraction of protein nanocrystals using a conventional scanning/transmission electron microscope (S/TEM). Randomly dispersed crystals are mapped, and dose-efficient diffraction patterns measured at each identified crystal position for structure determination. Each crystal is measured in a single orientation without rotation. The automated workflow is suitable for high-throughput applications with acquisition rates of up to 1 kHz at a high hit fraction. A dose fractionation scheme allows for minimization of radiation damage effects and inherently optimal acquisition settings. We demonstrate this method by solving the structure of crystalline granulovirus occlusion bodies and lysozyme to a resolution of 1.55 Å and 1.80 Å, respectively. Our method promises to provide rapid high-quality structure determination for many classes of materials with minimal sample consumption, using readily available instrumentation.We thank Djordje Gitaric for mechanical design work, Fabian Westermeier, David Pennicard, and Heinz Graafsma for adapting the Lambda detector for electron imaging, Anton Barty and Henry Chapman for many helpful discussions and critical reading of the manuscript, Thomas A. White for help with modifying CrystFEL for electron diffraction, and Michiel de Kock for help with image processing. We are indebted to Kay Grünewald and his research group for lending to us their cryo-transfer holder.

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“…MicroED has also proven to be a powerful method for the interrogation of small molecule structures, revealing atomic structures from seemingly amorphous powders 9 . Electron nanobeams 15 approximately 2 -150 nm in size can facilitate diffraction from challenging beam sensitive materials such as zeolites 8 , polymers 16,17 , organic small molecules 18 and proteins 19 , as well as more radiation hardy inorganic materials 20 .…”

Section: Main Text Introductionmentioning

confidence: 99%

Atomic structures determined from digitally defined nanocrystalline regions

Gallagher-Jones

Bustillo

Ophus

et al. 2019

Preprint

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AbstractNanocrystallography has transformed our ability to interrogate the atomic structures of proteins, peptides, organic molecules and materials. By probing atomic level details in ordered sub-10 nm regions of nanocrystals, approaches in scanning nanobeam electron diffraction extend the reach of nanocrystallography and mitigate the need for diffraction from large portions of one or more crystals. We now apply scanning nanobeam electron diffraction to determine atomic structures from digitally defined regions of beam-sensitive peptide nanocrystals. Using a direct electron detector, we record thousands of sparse diffraction patterns over multiple crystal orientations. We assign each pattern to a specific location on a single nanocrystal with axial, lateral and angular coordinates. This approach yields a collection of patterns that represent a tilt series across an angular wedge of reciprocal space: a scanning nanobeam diffraction tomogram. From this diffraction tomogram, we can digitally extract intensities from any desired region of a scan in real or diffraction space, exclusive of all other scanned points. Intensities from multiple regions of a crystal or from multiple crystals can be merged to increase data completeness and mitigate missing wedges. Merged intensities from digitally defined regions of two crystals of a segment from the OsPYL/RCAR5 protein produce fragment-based ab-initio solutions that can be refined to atomic resolution, analogous to structures determined by selected area electron diffraction. In allowing atomic structures to now be determined from digitally outlined regions of a nanocrystal, scanning nanobeam diffraction tomography breaks new ground in nanocrystallography.

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Electron diffraction determines molecular absolute configuration in a pharmaceutical nanocrystal

Cited by 168 publications

References 39 publications

The Crystal Structure of Orthocetamol Solved by 3D Electron Diffraction

The Crystal Structure of Orthocetamol Solved by 3D Electron Diffraction

Serial protein crystallography in an electron microscope

Atomic structures determined from digitally defined nanocrystalline regions

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