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Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps
Open accessPreprint — published as 10.1038/s41467-023-36732-5 · Paper page
Abstract
Advances in cryo-electron microscopy (cryoEM) and deep-learning guided protein structure prediction have expedited structural studies of protein complexes. However, methods for accurately determining ligand conformations are lacking. In this manuscript, we develop a tool for automatically determining ligand structures guided by medium-resolution cryoEM density. We show this method is robust at predicting ligands in maps as low as 6Å resolution, and is able to correct receptor sidechain errors. Combining this with a measure of placement confidence, and running on all protein/ligand structures in EMDB, we show that 58% of ligands replicate the deposited model, 16% confidently find alternate conformations, 22% have ambiguous density where multiple conformations might be present, and 4% are incorrectly placed. For five cases where our approach finds an alternate conformation with high confidence, high-resolution crystal structures validate our placement. This tool and the resulting analysis should prove critical in using cryoEM to investigate protein-ligand complexes.
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Metadata
- Authors
- Muenks, A., Zepeda, S., Zhou, G., Veesler, D., & DiMaio, F.
- Affiliations
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- DiMaio, Frank
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2022-08-17
- Volume
- 14
- Issue
- 1
- Pages
- 1164-1164
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9976687
- OpenAlex
- W4322733414
- Cited by
- 28
- References
- 1
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 7 · 2023: 2
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (T32GM008268, 1762114)
- Howard Hughes Medical Institute
- Burroughs Wellcome Fund
- Bill and Melinda Gates Foundation (OPP1156262)
- University of Washington (1762114)
- Fast Grants
- Defense Threat Reduction Agency (GRANT13030960)
- National Institute of General Medical Sciences (DGE-1762114, T32GM008268, R01GM123089)
- National Institute of Allergy and Infectious Diseases (DP1AI158186, 75N93022C00036, DP1AI158186 and 75N93022C00036, F31AI174573, OPP1156262)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- cryo-electron microscopy maps, protein-ligand complex, emerald, protein structure prediction
- MeSH terms
- Ligands, Mental Processes, Running, Cryoelectron Microscopy
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