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Cited by 36Enzyme Structure and FunctionProtein Structure and DynamicsCrystal structures of chemical compounds

Molecular replacement: tricks and treats

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Abergel, Chantal·2013·Acta Crystallographica Section D Biological Crystallography
DOI 10.1107/s0907444913015291PMC PMC3817689
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Abstract

Molecular replacement is the method of choice for X-ray crystallographic structure determination provided that suitable structural homologues are available in the PDB. Presently, there are ∼80 000 structures in the PDB (8074 were deposited in the year 2012 alone), of which ∼70% have been solved by molecular replacement. For successful molecular replacement the model must cover at least 50% of the total structure and the C α r.m.s.d. between the core model and the structure to be solved must be less than 2 Å. Here, an approach originally implemented in the CaspR server (http://www.igs.cnrs-mrs.fr/Caspr2/index.cgi) based on homology modelling to search for a molecular-replacement solution is discussed. How the use of as much information as possible from different sources can improve the model(s) is briefly described. The combination of structural information with distantly related sequences is crucial to optimize the multiple alignment that will define the boundaries of the core domains. PDB clusters (sequences with ≥30% identical residues) can also provide information on the eventual changes in conformation and will help to explore the relative orientations assumed by protein subdomains. Normal-mode analysis can also help in generating series of conformational models in the search for a molecular-replacement solution. Of course, finding a correct solution is only the first step and the accuracy of the identified solution is as important as the data quality to proceed through refinement. Here, some possible reasons for failure are discussed and solutions are proposed using a set of successful examples.

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  • Standard molecular replacement requires a template or homologous structure and performs best when the template is within 2 Å Cα RMSD of the target.

    “Standard molecular replacement strategies require 3D coordinates of a template/homologous structure and work best when the template is < 2 Å Cα RMSD from the target structure80.”

    From The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins (2024) · cites this paper as [80]

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Authors
Abergel, C.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Abergel, Chantal
ORCID
Abergel, Chantal
Venue
Acta Crystallographica Section D Biological Crystallography
Publisher
International Union of Crystallography (IUCr)
Published
2013-10-12
Volume
69
Issue
11
Pages
2167-2173
ISSN
0907-4449 (ISSN-L)
DOI
10.1107/s0907444913015291
PMC
PMC3817689
OpenAlex
W2007950357
Cited by
36
References
54
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 3 · 2015: 5 · 2014: 2
FWCI
0.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Crystallographica Section D Biological Crystallography (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Agence Nationale de la Recherche (ANR-08-BLAN-0089)
  • Centre National de la Recherche Scientifique
Topics
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Chemistry › Inorganic Chemistry › Crystal structures of chemical compounds
Keywords
molecular replacement, homology modeling, multiple sequence alignment, normal mode analysis, conformational model, protein subdomains, structural homology
MeSH terms
Amino Acid Sequence, Animals, Models, Molecular, Molecular Sequence Data, Sequence Alignment, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Protein Folding, Crystallography, X-Ray, Amino Acid Substitution, Escherichia coli Proteins, Databases, Protein

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