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ECOD: An Evolutionary Classification of Protein Domains
Open accessAbstract
Understanding the evolution of a protein, including both close and distant relationships, often reveals insight into its structure and function. Fast and easy access to such up-to-date information facilitates research. We have developed a hierarchical evolutionary classification of all proteins with experimentally determined spatial structures, and presented it as an interactive and updatable online database. ECOD (Evolutionary Classification of protein Domains) is distinct from other structural classifications in that it groups domains primarily by evolutionary relationships (homology), rather than topology (or "fold"). This distinction highlights cases of homology between domains of differing topology to aid in understanding of protein structure evolution. ECOD uniquely emphasizes distantly related homologs that are difficult to detect, and thus catalogs the largest number of evolutionary links among structural domain classifications. Placing distant homologs together underscores the ancestral similarities of these proteins and draws attention to the most important regions of sequence and structure, as well as conserved functional sites. ECOD also recognizes closer sequence-based relationships between protein domains. Currently, approximately 100,000 protein structures are classified in ECOD into 9,000 sequence families clustered into close to 2,000 evolutionary groups. The classification is assisted by an automated pipeline that quickly and consistently classifies weekly releases of PDB structures and allows for continual updates. This synchronization with PDB uniquely distinguishes ECOD among all protein classifications. Finally, we present several case studies of homologous proteins not recorded in other classifications, illustrating the potential of how ECOD can be used to further biological and evolutionary studies.
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“The ECOD homology level (“H level”) is a strict similarity criterion since it clusters domains even if they only have distant relationships.”
From Deep geometric representations for modeling effects of mutations on protein-protein binding affinity (2021) · cites this paper as [37]
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“we used the ECOD classifier [37] (file: “ecod.develop277.domains.txt”, version: “develop277”) to remove the similar complexes and ensure the training complexes share no ECOD homology domain with the benchmark datasets.”
From Deep geometric representations for modeling effects of mutations on protein-protein binding affinity (2021) · cites this paper as [37]
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Cites
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“In order to extend distant evolutionary relationships beyond the SCOP superfamily level in ECOD, we apply state of the art homology-inference algorithms both developed in our group [19,20] as well as by others [21,22], manually analyze and verify the suggested homologous links, and incorporate findings from literature.”
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“ECOD (Evolutionary Classification of Protein Domains) system (Cheng et al., 2014) was used to functionally classify 374 proteins, as detailed in Supplementary Table S9.”
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A survey of ADP-ribosyltransferase families in the pathogenic Legionella
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“We confirmed this imbalance in the most recent version of a semi-manually curated database, ECOD (version 20210511: develop280), which hierarchically classifies protein domains according to homology, reflecting their evolutionary relationship [26].”
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Hierarchical Analysis of Protein Structures: From Secondary Structures to Protein Units and Domains
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The RNA Silencing Suppressor P8 From High Plains Wheat Mosaic Virus is a Functional Tetramer
Hamo, S., Izhaki-Tavor, L. S., Tatineni, S., & Dessau, M. A. (2024) · Journal of Molecular Biology · doi:10.1016/j.jmb.2024.168870 · Cited by 2
DPAM-AI: a domain parser for AlphaFold models powered by artificial intelligence
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Unraveling the diversity of protein-carbohydrate interfaces: Insights from a multi-scale study
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“ECOD [35] and UbSRD [36] databases were used for the identification of integral UbL structures.”
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Function Diversity Within Folds and Superfamilies
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“They are distributed among 34 ECOD (Evolutionary Classification of Protein Domains [74]) family directories, with 2–76 files per directory (median 18).”
BackgroundRules for connectivity of secondary structure elements in protein: Two–layer αβ sandwiches
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Singh, J., Singh, J., Paliwal, K. K., Busch, A. W., & Zhou, Y. (2021) · IEEE Conference on Computational Intelligence in Bioinformatics and Computational Biology (CIBCB) · doi:10.1109/cibcb49929.2021.9562849 · Cited by 2
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Inferring Protein Domain Semantic Roles Using word2vecPreprint
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Conservation motifs - a novel evolutionary-based classification of proteinsPreprint
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“These include classification of proteins into functional annotations 3–5 , subcellular localization and organismal levels 6–8 , and classification of domains and functional sites 9– 11 .”
BackgroundMPDB: a unified multi-domain protein structure database integrating structural analogue detectionPreprint
Peng, C., Zhou, X., Xia, Y., Zhang, Y., & Zhang, G. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.27.466092 · Cited by 2
“ECOD (Evolutionary Classification of protein Domains) groups domains primarily by evolutionary relationships (homology) [7], which helps homology-based structure and function prediction and protein annotation by providing a pre-compiled search database.”
BackgroundIdentification of a covert evolutionary pathway between two protein folds
Chakravarty, D., Sreenivasan, S., Swint-Kruse, L., & Porter, L. L. (2022) · doi:10.1101/2022.12.08.519646 · Cited by 2
Sequence, Structure and Functional space of Drosophila de novo proteinsPreprint
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Cold seeps are hotspots of deep-sea nitrogen-loss driven by microorganisms across 21 phylaPreprint
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Exploiting protein language model sequence representations for repeat detectionPreprint
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Coenzyme-Protein Interactions since Early LifePreprint
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Modeling the structure-conditioned sequence landscape for large-scale protein design with TriFlowPreprint
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“We next annotated structural and functional properties for each residue in every ECOD domain.”
InfluentialThe X-ray structure of juvenile hormone diol kinase from the silkworm Bombyx mori
Guo, J., Keegan, R. M., Rigden, D. J., Erskine, P. T., Wood, S., Li, S., & Cooper, J. B. (2021) · Acta Crystallographica Section F Structural Biology Communications · doi:10.1107/s2053230x21012012 · Cited by 1
Exploring hydrophilic sequence space to search for uncharted foldable proteins by AlphaFold2
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The history of enzyme evolution embedded in metabolism
Corlett, T., Smith, H. B., Smith, E. A., Goldford, J. E., & Longo, L. M. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2609531123 · Cited by 3
Contrastive learning unites sequence and structure in a global representation of protein space
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“Indeed, it is for this reason that expert curation integrates both sequence and structure similarity (4–7).”
AFragmenter: schema-free, tuneable protein domain segmentation for AlphaFold protein structures
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“The inference of function based on domain homology helps researchers develop biological insights [5,6].”
Ancient Protein Folds in RNA Polymerase and Ribosomes
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TEDLH: domain HMMs for sensitive detection of remote homologues
Álvarez-Carreño, C., Petrov, A. S., Waman, V., Sillitoe, I., & Orengo, C. A. (2026) · Bioinformatics · doi:10.1093/bioinformatics/btag470 · Cited by 1
“Domains identified in experimentally determined structures from the Protein Data Bank (Berman et al. 2000) have been systematically classified and mapped onto protein sequences by resources such as CATH (Orengo et al. 1997), SCOP (Murzin et al. 1995), and ECOD (Cheng et al. 2014).”
Dudás, B., Berta, D., Jambrina, P. G., Buigues, P. J., Suardíaz, R., Gómez‐Coca, S., Deng, W., Brooks, B. R., Vértessy, B. G., & Rosta, E. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.6c10146 · Cited by 2
Structural Protein Function Prediction - A Comprehensive Review
Maghawry, H. A., Mostafa, M. G. M., Abdul-Aziz, M. H., & Gharib, T. F. (2015) · International Journal of Modern Education and Computer Science · doi:10.5815/ijmecs.2015.10.07 · Cited by 1
“Recently, a structural classification of loops in proteins (ArchDB) [14] and an evolutionary classification of protein domains (ECOD) [15] are presented.”
Kessel, A., Kolodny, R., & Ben‐Tal, N. (2017) · Israel Journal of Chemistry · doi:10.1002/ijch.201600133 · Cited by 1
Classification of twilight zone proteins using a structure-based phylogenetic approach
Taha, S. F. M., & Zakaria, Y. (2018) · IEEE Symposium on Computer Applications & Industrial Electronics (ISCAIE) · doi:10.1109/iscaie.2018.8405437 · Cited by 1
“SCOP have often used as a gold standard database for comparing protein structures [5]–[7].”
MethodDeep Learning of Protein Structural Classes: Any Evidence for an ‘Urfold’?
Jaiswal, M., Saleem, S., Kweon, Y., Draizen, E. J., Veretnik, S., Mura, C., & Bourne, P. E. (2020) · Systems and Information Engineering Design Symposium · doi:10.1109/sieds49339.2020.9106642 · Cited by 1
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Modelling structural rearrangements in proteins using Euclidean distance matrices
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Fold recognition by scoring protein maps using the congruence coefficient
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Limitations of the ABEGO-based backbone design: ambiguity between αα-corner and αα-hairpin
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“Analysis of helix–loop–helix fragments I composed a set of 29,397 non-redundant domain structures, which were a subset of the Evolutionary Classification Of protein Domains database (version develop238) culled by 40% sequence identity [16].”
BackgroundMethodDhondge, H., de Beauchêne, I. C., & Devignes, M. (2023) · Bioinformatics Advances · doi:10.1093/bioadv/vbad081 · Cited by 1
Structure and function of bacterial transcription regulators of the SorC family
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“The domains adopt a trefoil-resembling three-layer α/β/α sandwich architecture that can be divided into four parts, the core and three peripheral subdomains (P1, P2, P3; Figure 1c) [59].”
Functional Ambidexterity of an Ancient Nucleic Acid‐Binding Domain
Weil‐Ktorza, O., Naveh‐Tassa, S., Fridmann‐Sirkis, Y., Despotović, D., Cherukuri, K. P., Corlett, T., Levy, Y., Metanis, N., & Longo, L. M. (2025) · Angewandte Chemie · doi:10.1002/ange.202505188 · Cited by 1
Assessing Structural Classification Using AlphaFold2 Models Through ECOD ‐Based Comparative Analysis
Kawabata, T., & Kinoshita, K. (2025) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.26828
“The Dali program is a well-established structural comparison program with a history of usage [19], and it is also employed for the classification of the ECOD database [10].”
InfluentialAcharya, G., Kaur, G., & Subramanian, S. (2016) · Journal of Structural Biology · doi:10.1016/j.jsb.2016.08.004 · Cited by 1
Kinjo, A. R. (2018) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2018.01.019 · Cited by 1
“As observed in protein structure classification databases (Murzin et al., 1995; Orengo et al., 1997; Cheng et al., 2014), each protein family corresponds to a unique threedimensional fold, suggesting the existence of physical constraints imposed on protein sequences during the evolutionary process to maintain the fold…”
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Improved Protein Real-Valued Distance Prediction Using Deep Residual Dense Network (DRDN)
Geethu, S., & Vimina, E. R. (2022) · The Protein Journal · doi:10.1007/s10930-022-10067-4 · Cited by 1
“ECOD database classification [24, 25] is applied to ensure the prediction is made by the proposed method rather”
MethodEvolution of structural dynamics in bilobed proteinsPreprint
Gouridis, G., Muthahari, Y. A., de Boer, M., Tassis, K., Tsirigotaki, A., Zijlstra, N., Eleftheriadis, N., Xu, R., Zacharias, M., Griffith, D. A., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.10.19.344861 · Cited by 1
7-Transmembrane Helical (7TMH) Proteins: Pseudo-Symmetry and Conformational PlasticityPreprint
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The Evolution of Protein Folds by Creative DestructionPreprint
Álvarez-Carreño, C., Gupta, R. J., Petrov, A. S., & Williams, L. D. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.30.486258 · Cited by 1
“Profile-profile comparisons between folds in the ECOD database revealed regions of sequence similarity.”
MethodInfluentialA multi-domain connector links the outer membrane and cell wall in deep-branching bacteriaPreprint
von Kügelgen, A., van Dorst, S., Alva, V., & Bharat, T. A. M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.18.492506 · Cited by 1
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The protein structurome of Orthornavirae and its dark matterPreprint
Mutz, P., Camargo, A. P., Sahakyan, H., Neri, U., Butković, A., Wolf, Y. I., Krupovìč, M., Dolja, V. V., & Koonin, E. V. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.25.615016 · Cited by 1
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A Review on Protein Structure Classification
Sajithra, N., Ramyachitra, D., & Manikandan, P. (2019) · Lecture notes in computational vision and biomechanics · doi:10.1007/978-3-030-00665-5_10
Predicting Sequence Features, Function, and Structure of Proteins Using MESSA
Bhat, A., & Grishin, N. V. (2019) · Current Protocols in Bioinformatics · doi:10.1002/cpbi.84
“Evolutionary Classification of Protein Domains (ECOD): ECOD (Cheng et al., 2014; Schaeffer, Liao, & Grishin, 2018) classified domains based on a five-tier hierarchy, i.e., architecture (secondary structure), X-group (possible homology), H-group (definite homology), T-group (topology), and F-group (family).”
InfluentialProtein Structure Classification
Dawson, N. L., Das, S., Lees, J. G., & Orengo, C. A. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809633-8.20281-1
La nozione di felicità in Aristotele, "Retorica" I 5: due modi di trattare le opinioni notevoli
Natali, C. (1990) · Dialnet (Universidad de la Rioja)
Dunbrack, R. L. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727053949.793573294
Accurate Protein Domain Structure Annotation with DomainMapperPreprint
Manriquez‐Sandoval, E., & Fried, S. D. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.19.484986
“ECOD (evolutionary classification of protein domains) (Cheng et al., 2014; Schaeffer et al., 2016) is a relatively new domain classification system that emphasizes distant evolutionary relationships to construct a structural hierarchy and has been particularly useful for computational structure…”
BackgroundKoehl, P. (2017) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.732110432.793538904
Casadio, R. (2018) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.733716805.793549003
Faculty Opinions recommendation of The Pfam protein families database in 2019.
Stock, A. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.734287973.793568816
Huang, X., Yan, J. Y., Qu, W., Li, X., & Tan, J. (2022) · Current Chinese Science · doi:10.2174/2210298102666220509201554
Domain Structure Classifications
Waman, V., Cuff, A. L., & Orengo, C. A. (2022) · Springer eBooks · doi:10.1007/978-3-642-35943-9_414-1
A tissue injury repair pathway distinct but parallel to host pathogen defensePreprint
Liu, S., Hur, Y. H., Cai, X., Cong, Q., Yang, Y., Xu, C., Bilate, A. M. B., Gonzales, K. A. U., Cowley, C. J., Hurwitz, B. S., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.18.509515
“Evolutionary analysis of cytokines/receptors We retrieved the protein family containing IL24 from Pfam and ECOD databases (68, 69).”
MethodResearch on protein structure prediction and folding based on novel remote homologs recognitionPreprint
Zhao, K., Xia, Y., Zhang, F., Zhou, X., Li, S. Z., & Zhang, G. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.16.512404
The energetics and evolution of oxidoreductases in deep timePreprint
Nanda, V., McGuinness, K. N., Fehon, N., Feehan, R., Miller, M., Mutter, A. C., Nam, J., AbuSalim, J. E., Atkinson, J. T., Heidari, H., et al. (2023) · doi:10.22541/au.168439504.41026088/v1
Smug, B. J., Szczepaniak, K., Rocha, E. P. C., Dunin-Horkawicz, S., & Mostowy, R. J. (2023) · Research Square · doi:10.21203/rs.3.rs-3053497/v1
Missing-link fold reveals the evolutionary pathway between RNA polymerase and ribosomal proteinsPreprint
Yagi, S., & Tagami, S. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.05.547881
Additional file 1 of Protein language models can capture protein quaternary state
Avraham, O., Tsaban, T., Ben-Aharon, Z., Tsaban, L., & Schueler‐Furman, O. (2023) · Figshare · doi:10.6084/m9.figshare.24564069
Sequence, Structural and Functional Diversity of the Ubiquitous DNA/RNA-Binding Alba DomainPreprint
Jaiganesh, J., & Vembar, S. S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.16.589850
Sri, A. R. B. (2023) · International Journal of Science and Research (IJSR) · doi:10.21275/sr23411190029
In search for multifunctional lncRNAsPreprint
Iyengar, B. R. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.11.603032
“I obtained the embeddings vector for lncRNA encoded proteins and the sequences of protein domains in the ECOD database (Cheng et al. , 2014) that are 10 – 120 amino acids in length (thus excluding large domains that are unlikely to be found in short protein sequences).”
MethodRemote Homology Detection Via 3d Structural Comparison of Alphafold2-Predicted Tertiary StructuresPreprint
Kawabata, T., & Kinoshita, K. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4906071
A survey of ADP-ribosyltransferase families in the pathogenic LegionellaPreprint
Krysińska, M., Gradowski, M., Baranowski, B., Pawłowski, K., & Dudkiewicz, M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.30.605764
Protein Structure Classification in the Era of AlphaFold2
Waman, V., Dawson, N. L., Das, S., Lees, J., & Orengo, C. A. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95502-7.00047-6
Wang, J., Abrol, R., & Youkharibache, P. (2024) · Methods in molecular biology · doi:10.1007/978-1-0716-4213-9_19
Cazals, F., & Sarti, E. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.16.623929 · Cited by 1
“To understand our approach, it is important to recall that protein domain classification is a cornerstone of protein science [22, 23, 24].”
Damiri, N., Hadi, F. I. A., Khew, C., Quay, D. H. X., Muhammad, N. A. N., Mohd‐Assaad, N., Mat-Sharani, S., Lam, S. D., & Firdaus‐Raih, M. (2025) · Elsevier eBooks · doi:10.1016/b978-0-323-95502-7.00274-8
Kaur, L., Dhiman, R., Kaur, S., Gupta, L., Kaur, R. P., & Singh, H. (2025) · Elsevier eBooks · doi:10.1016/b978-0-323-95502-7.00170-6
Refinement and curation of homologous groups facilitated by structure prediction
Schaeffer, R. D., Pei, J., Zhang, J., Cong, Q., & Grishin, N. V. (2025) · Protein Science · doi:10.1002/pro.70074
“The Evolutionary Classification of protein Domains (ECOD) is a structural domain classification that has been actively updated for over a decade (Cheng et al. 2014; Schaeffer et al. 2017).”
Functional (Re)Annotation of Mycobacteroides Abscessus Proteome Using Ai-Based Structural FeaturesPreprint
Gnanasekar, P., Gambhir, S., Kinatukara, P., & Bhardwaj, A. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5162980
Karim, W., Alvi, R., Zaman, S. B., Abian, A. I., Raiaan, M. A. K., Mukta, S. H., Rashid, M. R. U., Islam, R., Sebastian, Y., & Azam, S. (2026) · Archives of Computational Methods in Engineering · doi:10.1007/s11831-026-10743-z · Cited by 7
“Datasets such as ProteinNet12 [126] and RCSB-PDB [127] are helpful in training models for protein structure generation and prediction tasks, while ECOD [128] and TOP 1773 SUPERFAMILIES [86] enhance model generalization across homologous protein families.”
Metadata
- Authors
- Cheng, H., Schaeffer, R. D., Liao, Y., Kinch, L. N., Pei, J., Shi, S., Kim, B.-H., & Grishin, N. V.
- Affiliations
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Grishin, Nick V.
- Venue
- PLoS Computational Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-12-04
- Volume
- 10
- Issue
- 12
- Pages
- e1003926
- ISSN
- 1553-734X (ISSN-L)
- 1553-7358
- PMC
- PMC4256011
- OpenAlex
- W1965827393
- Cited by
- 426
- References
- 61
- Citations by year
- 2026: 34 · 2025: 48 · 2024: 62 · 2023: 46 · 2022: 46 · 2021: 46 · 2020: 31 · 2019: 24 · 2018: 40 · 2017: 20 · 2016: 14 · 2015: 14
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute
- Welch Foundation (I-505)
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM094575, GM-094575)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- protein domain evolution, protein structure classification, homology, distant homologs, protein structure evolution, sequence families, PDB structures, protein domains, online databases
- MeSH terms
- Models, Molecular, Proteins, Protein Structure, Tertiary, Evolution, Molecular, Computational Biology, Databases, Protein
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