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Cited by 28Advanced Electron Microscopy Techniques and ApplicationsEnzyme Structure and FunctionProtein Structure and Dynamics

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Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps

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Muenks, Andrew, Zepeda, Samantha, Zhou, Guangfeng, Veesler, David, DiMaio, Frank·2023·Nature Communications
DOI 10.1038/s41467-023-36732-5PMC PMC9976687

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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 EMERALD, a tool for automatically determining ligand structures guided by medium-resolution cryoEM density. We show this method is robust at predicting ligands along with surrounding side chains in maps as low as 4.5 Å local resolution. Combining this with a measure of placement confidence and running on all protein/ligand structures in the EMDB, we show that 57% of ligands replicate the deposited model, 16% confidently find alternate conformations, 22% have ambiguous density where multiple conformations might be present, and 5% are incorrectly placed. For five cases where our approach finds an alternate conformation with high confidence, high-resolution crystal structures validate our placement. EMERALD and the resulting analysis should prove critical in using cryoEM to solve 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
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-03-01
Volume
14
Issue
1
Pages
1164-1164
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-36732-5
PMC
PMC9976687
OpenAlex
W4322733414
Cited by
28
References
4
Citations by year
2026: 6 · 2025: 13 · 2024: 7 · 2023: 2
FWCI
2.47
Type
journal article
Language
en
Open access
Licence
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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