Visualizing drug binding interactions using microcrystal electron diffraction
(2020) In Communications Biology 3(1).- Abstract
Visualizing ligand binding interactions is important for structure-based drug design and fragment-based screening methods. Rapid and uniform soaking with potentially reduced lattice defects make small macromolecular crystals attractive targets for studying drug binding using microcrystal electron diffraction (MicroED). However, so far no drug binding interactions could unambiguously be resolved by electron diffraction alone. Here, we use MicroED to study the binding of a sulfonamide inhibitor to human carbonic anhydrase isoform II (HCA II). We show that MicroED data can efficiently be collected on a conventional transmission electron microscope from thin hydrated microcrystals soaked with the clinical drug acetazolamide (AZM). The data... (More)
Visualizing ligand binding interactions is important for structure-based drug design and fragment-based screening methods. Rapid and uniform soaking with potentially reduced lattice defects make small macromolecular crystals attractive targets for studying drug binding using microcrystal electron diffraction (MicroED). However, so far no drug binding interactions could unambiguously be resolved by electron diffraction alone. Here, we use MicroED to study the binding of a sulfonamide inhibitor to human carbonic anhydrase isoform II (HCA II). We show that MicroED data can efficiently be collected on a conventional transmission electron microscope from thin hydrated microcrystals soaked with the clinical drug acetazolamide (AZM). The data are of high enough quality to unequivocally fit and resolve the bound inhibitor. We anticipate MicroED can play an important role in facilitating in-house fragment screening for drug discovery, complementing existing methods in structural biology such as X-ray and neutron diffraction.
(Less)
- author
- Clabbers, Max T.B. ; Fisher, S. Zoë LU ; Coinçon, Mathieu ; Zou, Xiaodong and Xu, Hongyi
- organization
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Communications Biology
- volume
- 3
- issue
- 1
- article number
- 417
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:32737395
- scopus:85088870142
- ISSN
- 2399-3642
- DOI
- 10.1038/s42003-020-01155-1
- language
- English
- LU publication?
- yes
- id
- b13d0440-4719-49fc-9a3e-93b44982a869
- date added to LUP
- 2020-08-07 10:36:28
- date last changed
- 2024-05-15 15:48:42
@article{b13d0440-4719-49fc-9a3e-93b44982a869,
abstract = {{<p>Visualizing ligand binding interactions is important for structure-based drug design and fragment-based screening methods. Rapid and uniform soaking with potentially reduced lattice defects make small macromolecular crystals attractive targets for studying drug binding using microcrystal electron diffraction (MicroED). However, so far no drug binding interactions could unambiguously be resolved by electron diffraction alone. Here, we use MicroED to study the binding of a sulfonamide inhibitor to human carbonic anhydrase isoform II (HCA II). We show that MicroED data can efficiently be collected on a conventional transmission electron microscope from thin hydrated microcrystals soaked with the clinical drug acetazolamide (AZM). The data are of high enough quality to unequivocally fit and resolve the bound inhibitor. We anticipate MicroED can play an important role in facilitating in-house fragment screening for drug discovery, complementing existing methods in structural biology such as X-ray and neutron diffraction.</p>}},
author = {{Clabbers, Max T.B. and Fisher, S. Zoë and Coinçon, Mathieu and Zou, Xiaodong and Xu, Hongyi}},
issn = {{2399-3642}},
language = {{eng}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Communications Biology}},
title = {{Visualizing drug binding interactions using microcrystal electron diffraction}},
url = {{http://dx.doi.org/10.1038/s42003-020-01155-1}},
doi = {{10.1038/s42003-020-01155-1}},
volume = {{3}},
year = {{2020}},
}