High-throughput structures of protein-ligand complexes at room temperature using serial femtosecond crystallography
© Tadeo Moreno-Chicano et al. 2019..
High-throughput X-ray crystal structures of protein-ligand complexes are critical to pharmaceutical drug development. However, cryocooling of crystals and X-ray radiation damage may distort the observed ligand binding. Serial femtosecond crystallography (SFX) using X-ray free-electron lasers (XFELs) can produce radiation-damage-free room-temperature structures. Ligand-binding studies using SFX have received only modest attention, partly owing to limited beamtime availability and the large quantity of sample that is required per structure determination. Here, a high-throughput approach to determine room-temperature damage-free structures with excellent sample and time efficiency is demonstrated, allowing complexes to be characterized rapidly and without prohibitive sample requirements. This yields high-quality difference density maps allowing unambiguous ligand placement. Crucially, it is demonstrated that ligands similar in size or smaller than those used in fragment-based drug design may be clearly identified in data sets obtained from <1000 diffraction images. This efficiency in both sample and XFEL beamtime opens the door to true high-throughput screening of protein-ligand complexes using SFX.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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| Enthalten in: |
IUCrJ - 6(2019), Pt 6 vom: 01. Nov., Seite 1074-1085 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Moreno-Chicano, Tadeo [VerfasserIn] |
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| Links: |
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| Themen: |
Damage-free structures |
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| Anmerkungen: |
Date Revised 19.10.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1107/S2052252519011655 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM303128240 |
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| 520 | |a © Tadeo Moreno-Chicano et al. 2019. | ||
| 520 | |a High-throughput X-ray crystal structures of protein-ligand complexes are critical to pharmaceutical drug development. However, cryocooling of crystals and X-ray radiation damage may distort the observed ligand binding. Serial femtosecond crystallography (SFX) using X-ray free-electron lasers (XFELs) can produce radiation-damage-free room-temperature structures. Ligand-binding studies using SFX have received only modest attention, partly owing to limited beamtime availability and the large quantity of sample that is required per structure determination. Here, a high-throughput approach to determine room-temperature damage-free structures with excellent sample and time efficiency is demonstrated, allowing complexes to be characterized rapidly and without prohibitive sample requirements. This yields high-quality difference density maps allowing unambiguous ligand placement. Crucially, it is demonstrated that ligands similar in size or smaller than those used in fragment-based drug design may be clearly identified in data sets obtained from <1000 diffraction images. This efficiency in both sample and XFEL beamtime opens the door to true high-throughput screening of protein-ligand complexes using SFX | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a X-ray crystallography | |
| 650 | 4 | |a X-ray free-electron lasers | |
| 650 | 4 | |a damage-free structures | |
| 650 | 4 | |a high throughput | |
| 650 | 4 | |a ligand binding | |
| 650 | 4 | |a serial femtosecond crystallography | |
| 700 | 1 | |a Ebrahim, Ali |e verfasserin |4 aut | |
| 700 | 1 | |a Axford, Danny |e verfasserin |4 aut | |
| 700 | 1 | |a Appleby, Martin V |e verfasserin |4 aut | |
| 700 | 1 | |a Beale, John H |e verfasserin |4 aut | |
| 700 | 1 | |a Chaplin, Amanda K |e verfasserin |4 aut | |
| 700 | 1 | |a Duyvesteyn, Helen M E |e verfasserin |4 aut | |
| 700 | 1 | |a Ghiladi, Reza A |e verfasserin |4 aut | |
| 700 | 1 | |a Owada, Shigeki |e verfasserin |4 aut | |
| 700 | 1 | |a Sherrell, Darren A |e verfasserin |4 aut | |
| 700 | 1 | |a Strange, Richard W |e verfasserin |4 aut | |
| 700 | 1 | |a Sugimoto, Hiroshi |e verfasserin |4 aut | |
| 700 | 1 | |a Tono, Kensuke |e verfasserin |4 aut | |
| 700 | 1 | |a Worrall, Jonathan A R |e verfasserin |4 aut | |
| 700 | 1 | |a Owen, Robin L |e verfasserin |4 aut | |
| 700 | 1 | |a Hough, Michael A |e verfasserin |4 aut | |
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